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Introduction: Breast cancer (BC) presents diverse malignancies with varying biological and clinical behaviors, driven by an interplay between cancer cells and tumor microenvironment. Deciphering these interactions is crucial for personalized diagnostics and treatment. This study explores the prognostic impact of tumor proliferation and immune response patterns, assessed by computational pathology indicators, on breast cancer-specific survival (BCSS) models in estrogen receptor-positive HER2-negative (ER+HER2-) and triple-negative BC (TNBC) patients., Materials and Methods: Whole-slide images of tumor surgical excision samples from 252 ER+HER2- patients and 63 TNBC patients stained for estrogen and progesterone receptors, Ki67, HER2, and CD8 were analyzed. Digital image analysis (DIA) was performed for tumor tissue segmentation and quantification of immunohistochemistry (IHC) markers; the DIA outputs were subsampled by hexagonal grids to assess the spatial distributions of Ki67-positive tumor cells and CD8-positive (CD8+) cell infiltrates, expressed as Ki67-entropy and CD8-immunogradient indicators, respectively. Prognostic models for BCSS were generated using multivariable Cox regression analysis, integrating clinicopathological and computational IHC indicators., Results: In the ER+HER2- BC, multivariable Cox regression revealed that high CD8+ density within the tumor interface zone (IZ) (HR: 0.26, p = 0.0056), low immunodrop indicator of CD8+ density (HR: 2.93, p = 0.0051), and low Ki67-entropy (HR: 5.95, p = 0.0.0061) were independent predictors of better BCSS, while lymph node involvement predicted worse BCSS (HR: 3.30, p = 0.0013). In TNBC, increased CD8+ density in the IZ stroma (HR: 0.19, p = 0.0119) and Ki67-entropy (HR: 3.31, p = 0.0250) were independent predictors of worse BCSS. Combining these independent indicators enhanced prognostic stratification in both BC subtypes., Conclusions: Computational biomarkers, representing spatial properties of the tumor proliferation and immune cell infiltrates, provided independent prognostic information beyond conventional IHC markers in BC. Integrating Ki67-entropy and CD8-immunogradient indicators into prognostic models can improve patient stratification with regard to BCSS., Competing Interests: The authors declare no competing interests related to this manuscript. However, it should be noted that Arvydas Laurinavicius, Allan Rasmusson, and Dovile Zilenaite-Petrulaitiene are co-authors of “Automated Tumor-Stroma Interface Zone Detection for Anti-tumor Immune Response Assessment by Immunogradient Indicators,” which has been submitted by Vilnius University for an international patent related to the immunogradient indicators (No. PCT/IB2020/053396, International Bureau of the World Intellectual Property Organization). This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Zilenaite-Petrulaitiene et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu 9 S 8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: There may be potential associations between various pathogens, antibody immune responses, and breast cancer (BC), but the specific mechanisms and causal relationships remain unclear., Methods: First, multiple Mendelian randomization (MR) methods were used for univariable MR analysis to explore potential causal relationships between 34 antibody immune responses (related to 12 pathogens), 46 antibody immune responses (related to 13 pathogens), antibody responses post-COVID-19 vaccination, 731 immune cell types, and various BC subtypes (including overall BC, ER-positive, ER-negative, Luminal A, Luminal B, Luminal B HER2-negative, HER2-positive, and triple-negative BC). The primary results were then subjected to reverse MR analysis, heterogeneity testing using Cochran's Q, and horizontal pleiotropy testing. Robust findings were further used to design mediation pathways involving antibody immune responses, immune cells, and BC. After adjusting the effect estimates using multivariable MR (MVMR), a two-step mediation analysis was conducted to explore mediation pathways and mediation proportions. Finally, linkage disequilibrium score regression (LDSC) was applied to analyze the genetic correlation between phenotypes along mediation pathways, and cross-phenotype association analysis (CPASSOC) was performed to identify pleiotropic SNPs among three phenotypes along these pathways. Bayesian colocalization tests were conducted on pleiotropic SNPs using the multiple-trait-coloc (moloc)., Results: We identified potential causal relationships between 15 antibody immune responses to 8 pathogens (Hepatitis B virus, Herpes Simplex Virus 2, Human Herpesvirus 6, Polyomavirus 2, BK polyomavirus, Cytomegalovirus, Helicobacter pylori, Chlamydia trachomatis), 250 immune cell phenotypes, and various BC subtypes. MVMR-adjusted mediation analysis revealed four potential mediation pathways. LDSC results showed no significant genetic correlation between phenotypes pairwise. CPASSOC analysis identified two potential mediation pathways with common pleiotropic SNPs (rs12121677, rs281378, rs2894250). However, none of these SNPs passed the Bayesian colocalization test by moloc. These results excluded horizontal pleiotropy, stabilizing MR analysis results., Conclusion: This study utilized MR methods to analyze potential causal relationships between various antibody immune responses, immune cell types, and BC subtypes, identifying four potential regulatory mediation pathways. The findings of this study offer potential targets and research directions for virus-related and immunotherapy-related studies, providing a certain level of theoretical support. However, limitations such as GWAS sample size constraints and unclear specific pathophysiological mechanisms need further improvement and validation in future studies., Competing Interests: Declarations Ethics approval and consent to participate Since this study utilized de-identified public data, there was no need for additional approval. All original ethical approvals are available in the original literature and on the website. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Only a subset of patients with breast cancer responds to immune checkpoint blockade (ICB). To better understand the underlying mechanisms, we analyze pretreatment biopsies from patients in the I-SPY 2 trial who receive neoadjuvant ICB using multiple platforms to profile the tumor microenvironment. A variety of immune cell populations and markers of immune/cytokine signaling associate with pathologic complete response (pCR). Interestingly, these differ by breast cancer receptor subtype. Measures of the spatial distributions of immune cells within the tumor microenvironment, in particular colocalization or close spatial proximity of PD-1 + T cells with PD-L1 + cells (immune and tumor cells), are significantly associated with response in the overall cohort as well as the in the triple negative (TN) and HR + HER2 - subtypes. Our findings indicate that biomarkers associated with immune cell signaling, immune cell densities, and spatial metrics are predictive of neoadjuvant ICB efficacy in breast cancer., Competing Interests: Declaration of interests J.W. reports honoraria from DAVA Oncology; consults for Baylor College of Medicine; has ownership in Theralink; and is co-inventor of the RPPA technology, and phospho-HER2 and -EGFR response predictors with filed patents. C.H. is an employee of Akoya Biosciences. R.N. reports grants from Quantum Leap, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics outside the submitted work; and personal fees from Aduro, AstraZeneca, Athenex, Celgene, Daiichi Sankyo, G1 Therapeutics, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma, and Syndax. M.C.L. reports support from Eisai, Genentech, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro. D.Y. reports unrelated support from Boehringer Ingelheim. A.M.D. reports honoraria or consulting for Pfizer and Context Therapeutics and reports support from Novartis, Pfizer, Genentech, Calithera, and Menarini. L.P. reports consulting fees and honoraria for advisory board participation from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, and Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Bristol-Myers Squibb. D.A.B. is co-owner of Berry Consultants LLC, a company that designs adaptive clinical trials (including I-SPY2). E.F.P. reports leadership, stock/ownership, consulting/advisory, and travel funds from Perthera and Ceres Nanosciences; stock and consulting/advisory for Theralink Technologies, Inc; support from Ceres Nanosciences, GlaxoSmithKline, AbbVie, Symphogen, Genentech, SpringWorks Therapeutics, and Deciphera Therapeutics; and patents/royalties from NIH and filed patents for p-HER2 and p-EGFR response predictors. L.v.V. is a co-inventor of the MammaPrint signature and a part-time employee and stockholder of Agendia NV. L.E. is an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative (QLHC), has received grant support from QLHC for the I-SPY2 trial, and is on the Blue Cross/Blue Shield Medical Advisory Panel., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tumor-associated macrophages (TAMs) drive the protumorigenic responses and facilitate tumor progression via matrix remodeling, angiogenesis, and immunosuppression by interacting with extracellular matrix proteins via integrins. However, the expression dynamics of integrin and its correlation with TAM functional programming in the tumors remain unexplored. In this study, we examined surface integrins' role in TAM recruitment and phenotypic programming in a 4T1-induced murine breast tumor model. Our findings show that integrin α5β1 is upregulated in CD11b+Ly6Chi monocytes in the bone marrow and blood by day 10 after tumor induction. Subsequent analysis revealed elevated integrin α5β1 expression on tumor-infiltrating monocytes (Ly6ChiMHC class II [MHCII]low) and M1 TAMs (F4/80+Ly6ClowMHCIIhi), whereas integrin αvβ3 was predominantly expressed on M2 TAMs (F4/80+Ly6ClowMHCIIlow), correlating with higher CD206 and MERTK expression. Gene profiling of cells sorted from murine tumors showed that CD11b+Ly6G-F4/80+α5+ TAMs had elevated inflammatory genes (IL-6, TNF-α, and STAT1/2), whereas CD11b+Ly6G-F4/80+αv+ TAMs exhibited a protumorigenic phenotype (IL-10, Arg1, TGF-β, and STAT3/6). In vitro studies demonstrated that blocking integrin α5 and αv during macrophage differentiation from human peripheral blood monocytes reduced cell spreading and expression of CD206 and CD163 in the presence of specific matrix proteins, fibronectin, and vitronectin. Furthermore, RNA sequencing data analysis (GEO dataset: GSE195857) from bone marrow-derived monocytes and TAMs in 4T1 mammary tumors revealed differential integrin α5 and αv expression and their association with FAK and SRC kinase. In line with this, FAK inhibition during TAM polarization reduced SRC, STAT1, and STAT6 phosphorylation. In conclusion, these findings underscore the crucial role of integrins in TAM recruitment, polarization, and reprogramming in tumors., (Copyright © 2024 by The American Association of Immunologists, Inc.)

The complex heterogeneity of tumor microenvironment (TME) of triple-negative breast cancer (TNBC) presents a significant obstacle to cytotoxic immune response and successful treatment, building up one of the most hostile oncological phenotypes. Among the most abundant TME components, tumor-associated macrophages (TAMs) have pivotal pro-tumoral functions, involving discordant roles for the nuclear factor kappa-B (NF-κB) transcription factors and directing to higher levels of pathway complexity. In both resting macrophages and TAMs, we recently revealed the existence of the uncharacterized NF-κB p65/p52 dimer. In the present study, we demonstrated its enhanced active nuclear localization in TAMs and validated selected immune target genes as directly regulated by dimer binding on DNA sequences. We demonstrated by ChIP-qPCR that p65/p52 enrichment on HSPG2 and CSF-1 regulatory regions is strictly dependent on macrophage polarization and tumor environment. Our data provide novel mechanisms of transcriptional regulation in TAMs, orchestrated by the varied and dynamic nature of NF-κB combinations, which needs to be considered when targeting this pathway in cancer therapies. Our results offer p65/p52, together with identified regulatory regions on genes impacting macrophage behavior and tumor biology, as novel molecular targets for TNBC, aimed at modulating TAMs functions towards anti-tumoral phenotypes and thus improving cancer treatment outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neoadjuvant therapy with trastuzumab, pertuzumab and paclitaxel (THP) has significantly improved the prognosis of patients with human epidermal growth factor receptor 2 (HER2) + breast cancer (BC). However, there remains a subset of non-responsive patients. Thus, this study sought to identify key regulators of THP neoadjuvant therapy resistance and potential targets to sensitize sensitivity., Methods: The Cancer Genome Atlas database, Gene Expression Omnibus and membrane protein database were used to identify the key regulator of THP neoadjuvant resistance. The biological functions and mechanisms of delta-like 4 proteins (DLL4) in THP therapy resistance were investigated in vitro and in vivo using the bioinformatic analysis, multiplex immunofluorescence, flow cytometry, sphere formation assays and chromatin immunoprecipitation, etc. Furthermore, DLL4-targeted chimeric antigen receptor (CAR)-T cells were established to sensitize THP therapy., Results: DLL4 was identified as a key target in THP neoadjuvant therapy resistance for HER2 + BC. Mechanistically, DLL4 + tumor cells exhibited enhanced stemness and resistance to the THP neoadjuvant chemotherapy. Additionally, soluble DLL4 can split away from tumor cells and diffuse into the stroma, where it can activate the Notch signaling pathway in neutrophils, inducing the formation and release of neutrophil extracellular traps (NETs) by regulating the transcription of MPO, PDIA4 and ELANE. This led to the exclusion of lymphocyte infiltration, thereby enhancing therapy resistance. What is more, we designed a DLL4-targeted CAR-T to eliminate DLL4 + tumor cells and reverse the resistant status., Conclusions: Our study revealed novel functions of DLL4 in cell stemness and immune infiltration, including NET formation and T cell exclusion, which collectively contributed to THP neoadjuvant therapy resistance in HER2 + BC. Furthermore, we provided a CAR-T-based therapy to sensitize the THP neoadjuvant therapy., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Breast cancer (BRCA) is among the most prevalent cancers and is responsible for numerous patient fatalities. Immunotherapy has emerged as a promising approach to cancer treatment. Recent studies have identified Siglec-15 as a novel immune target that plays a crucial role in tumor immune evasion, suggesting its potential significance in BRCA. We utilized databases such as TCGA to investigate the relevance of SIGLEC15 in BRCA. The expression of the Siglec-15 protein in 74 breast cancer patients was detected using immunohistochemistry, and its association with clinicopathological features and overall survival was evaluated. The co-expression of Siglec-15, CD68, CK, and CD8 in BRCA tissues was identified through multiplex immunofluorescence staining. Our study revealed that SIGLEC15 expression in BRCA was significantly elevated compared to adjacent normal tissues. Kaplan-Meier analysis identified SIGLEC15 as a prognostic protective factor. According to the receiver operating characteristic curve analysis, SIGLEC15 could predict the luminal subtype of BRCA. Enrichment analysis demonstrated that SIGLEC15 involves various biological pathways, including immunity, metabolism, tumors, and infectious diseases. Correlation analysis revealed an association between SIGLEC15 expression and immune infiltration in BRCA. We also confirmed that the Siglec-15 protein is expressed in cancer cells, tumor-infiltrating T cells, and macrophages in BRCA tissues, significantly higher levels than in normal breast tissues. Consequently, SIGLEC15 correlates with tumor immune infiltration, molecular subtypes, and BRCA progression and prognosis. However, further research is required to elucidate the role of SIGLEC15 in breast cancer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Indoleamine 2,3-dioxygenase 1 (IDO1) plays an important role in the initiation and progression of breast cancer. DNA promoter methylation status has the potential to be used as a biomarker for predicting the response to immunotherapy. This study aimed to investigate the biological and clinical significance of IDO1 promoter methylation in breast cancer. We analyzed IDO1 promoter methylation and its relationship with survival, patient prognosis, immune cell infiltration, immune-related pathways, and the expression of key immunomodulators via bioinformatics methods in The Cancer Genome Atlas (TCGA) breast cancer cohort (779 samples). Furthermore, the IDO1 promoter methylation status and expression of the IDO1 gene in the basal subtype of breast cancer were investigated in vitro via a methylation-specific PCR (MSP) assay and quantitative polymerase chain reaction (qPCR). The IDO1 promoter was significantly hypomethylated in the basal subtype of breast cancer tissues compared with normal adjacent tissues, and this effect was correlated with high expression of IDO1, resulting in abundant immune cell infiltration, activation of immune-related pathways, and upregulation of key immunomodulators. The influence of IDO1 promoter hypomethylation on the prognosis of patients with breast cancer was also investigated. The promoter hypomethylation of IDO1 in the basal subtype of breast cancer and its correlation with high expression of IDO1 were also investigated in vitro. Our results showed that IDO1 promoter methylation is vital for regulating its expression, which leads to the development of a tumor microenvironment in breast cancer. IDO1 promoter methylation and expression are associated with prognosis, immune cell infiltration, immune-related pathways, and immunomodulator expression in breast cancer. Our findings provide evidence for the validation of IDO1 promoter methylation as a promising biomarker to predict responses to immune checkpoint inhibitors in patients with breast cancer., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval The use of the public data was approved by TCGA. Consent for publication Not applicable., (© 2024. The Author(s).)

Ferroptosis has shown great potential in activating antitumor immunity. However, the cunning tumor cells can evade ferroptosis by increasing the efflux of iron and promoting the production of the reductant glutathione to mitigate oxidative stress. Herein, a multifunctional exosome loaded with manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron metabolism homeostasis and redox homeostasis to enhance tumor immunotherapy. The efficient transport of MnIO by exosomes and the inhibition of iron exocytosis by GW4869 led to a high retention of up to 29.57% ID/g for iron in the tumors. Such a high retention of iron, in combination with the BSO-induced disruption of the redox homeostasis, effectively promotes the ferroptosis of tumor cells. Consequently, the multifunctional exosomes that noticeably enhance ferroptosis by dual homeostasis disruption provoke the cGAS-STING-based antitumor immune response and effectively suppress tumor growth and lung metastasis in orthotopic breast cancer.

This review shows how mammary stem cells (MaSCs) influence breast development, breastfeeding, and breast cancer risk. MaSCs, which can differentiate into various cell types, are vital for breast tissue health, but also disease development in breast tissue. Research shows that breastfeeding affects MaSCs, offering protection against breast cancer through various mechanisms. Hormonal changes such as increased prolactin concentration, oxytocin secretion, lower progesterone levels, and reduced exposure to estrogen during lactation promote apoptosis in potential cancer cells, boost immune surveillance, and modulate inflammation. Key findings reveal that pregnancy at an earlier age and extended breastfeeding reduce MaSC numbers, lowering cancer risk. Additionally, breastfeeding induces various epigenetic changes, such as DNA methylation and histone modification, which provide long-term protection against the development of cancer. Components of breast milk, like alpha-lactalbumin and lactoferrin, contribute by promoting cancer cell apoptosis and inhibiting tumor growth. The dual benefits of breastfeeding are reduced breast cancer risk for mothers and immunological advantages for infants. Multicenter epidemiology research has focused particular attention on longer breastfeeding duration associated with a reduced risk of triple-negative breast cancer. This review offers comprehensive evidence that breastfeeding protects against breast cancer through various biological, hormonal, and molecular mechanisms, showing the importance of promoting breastfeeding as a natural cancer prevention method. This article reviews the role of mammary stem cells in breast development, lactation, and breast cancer.

Immune composition within the tumor microenvironment (TME) plays a central role in the propensity of cancer cells to metastasize and respond to therapy. Previous studies have suggested that the metastatic TME is immune-suppressed. However, limited accessibility to multiple metastatic sites within patients has made assessing the immune TME difficult in the context of multiorgan metastases. We utilized a rapid postmortem tissue collection protocol to assess the immune composition of numerous sites of breast cancer metastasis and paired tumor-free tissues. Metastases had comparable immune cell densities and compositions to paired tumor-free tissues of the same organ type. In contrast, immune cell densities in both metastatic and tumor-free tissues differed significantly between organ types, with lung immune infiltration being consistently greater than that in the liver. These immune profiling results were consistent between flow cytometry and multiplex immunofluorescence-based spatial analysis. Furthermore, we found that granulocytes were the predominant tumor-infiltrating immune cells in lung and liver metastases, and these granulocytes comprised most PD-L1-expressing cells in many tissue sites. We also identified distinct potential mechanisms of immunosuppression in lung and liver metastases, with the lung having increased expression of PD-L1+ antigen-presenting cells and the liver having higher numbers of activated regulatory T cells and HLA-DRlow monocytes. Together, these results demonstrate that the immune contexture of metastases is dictated by organ type and that immunotherapy strategies may benefit from unique tailoring to the tissue-specific features of the immune TME., (©2024 American Association for Cancer Research.)

Metastasis to the lungs is a leading cause of death for patients with breast cancer. Therefore, effective therapies are urgently needed to prevent and treat lung metastasis. In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness, and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in patients with breast cancer.  Significance: NQO1 stabilizes and promotes the secretion of PPIA to activate CD147 in neutrophils and stimulate NET formation, promoting breast cancer lung metastasis and providing therapeutic targets for this fatal condition., (©2024 American Association for Cancer Research.)

Background: Lymphocyte antigen 6 complex, locus E (Ly6E) has been initially demonstrated to involve in T cell activity and impair viral infectivity. Recently, high expression levels of Ly6E have been reported in tumor microenvironment (TME) of various types of cancers. However, the immunoregulatory mechanism of Ly6E manipulating TME remains unknown., Methods: TCGA database and Kaplan-Meier plotter database were used to evaluate the correlation between Ly6E expression levels and cancer patient survival. After analyzing Ly6E expression levels in human breast cancer tissues and tumor cell lines, we generated Ly6E knockout (KO) and overexpression (OE) mouse cell lines. Cell proliferation ability in vitro and the ability of growth and metastasis in mouse tumor models were compared between KO/OE and wild-type tumor cells. On day 7 after tumor implantation, tumor tissues were separated for flow cytometric assay, bulk RNA sequencing and single-cell RNA sequencing (ScRNA-seq). The role of Ly6E-expressing tumor cell on macrophage was analyzed in vitro., Results: Our result surprisingly found that high Ly6E expression levels were associated with CD8 + T cell exclusion in tumor tissues and resistance to immunotherapy. Our data showed that knockout of Ly6E in tumor cells prompts tumor regression and inhibits tumor metastases, and Ly6E-OE tumor cells vice versa. The enhanced anti-tumor effect of Ly6E knockout in tumor cells was dependent on T cell response and formed long-lasting memory. The increase in the CD8 + T-cell infiltration into the tumor islet of Ly6E-KO tumors confirmed the role of Ly6E on T cell exclusion. ScRNA-seq analysis showed that M2 macrophages are particularly abundant in the Ly6E-expressing tumor tissues, especially M2-4 macrophage cluster identified by high levels of Arg-1, indicates that Ly6E-expressing tumor cells might restrict T cell infiltration via M2 macrophages. Moreover, in vitro assay showed that cell culture media derived from Ly6E-positive tumor cells promoted macrophage migration and M2 polarization., Conclusion: Our study illuminated that Ly6E-expressing tumor cells facilitated the accumulation of M2 macrophages in TME, which contributes to CD8 + T cell exclusion and provides new insights for improving efficacy of cancer immunotherapy., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs), a crucial component of the tumor microenvironment (TME), are closely associated to the growth, invasion, metastasis, and prognosis of breast cancer. Targeting TAMs is considered to be a potential new strategy for improving the therapeutic efficacy of breast cancer. TAMs interact with breast cancer cells and influence the development and progression of various breast cancer subtypes through multiple pathways, including the secretion of proteins, cytokines, chemokines, and exosomes. Anti-breast cancer drugs targeting TAMs and emerging therapies are continually being discovered. This article explores the effects and mechanisms of TAMs in different breast cancer subtypes, examines the anti-breast cancer effects of herbal extracts and their active ingredients targeting TAMs, and introduces new technologies such as nano-agents, gene therapy, and immunocellular therapy that target TAMs. These therapeutic strategies targeting TAMs may be critical in improving the therapeutic efficacy and prognosis of breast cancer patients.

Identification of the novel HLA-A*24:02:01:144Q allele that differs from HLA-A*24:02:01:01 at one position in intron 4., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Breast cancer remains a leading cause of cancer-related deaths among women worldwide, highlighting the need for novel therapeutic strategies. Trophoblast cell surface antigen 2 (Trop-2), a type I transmembrane glycoprotein highly expressed in various solid tumors including all subtypes of breast cancer, has emerged as a promising target for cancer therapy. This review focuses on recent advancements in Trop-2-targeted antibody-drug conjugates (ADCs) for breast cancer treatment. We comprehensively analyzed the structure and mechanism of action of ADCs, as well as the role of Trop-2 in breast cancer progression and prognosis. Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. We systematically reviewed the ongoing clinical studies of these ADCs, highlighting their efficacy and safety profiles. Furthermore, we explored the potential of combining Trop-2-targeted ADCs with other therapeutic modalities, including immunotherapy, targeted therapies, and small molecule inhibitors. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tong, Fan, Liu and Liang.)

Background: Cell death mechanisms are integral to the pathogenesis of breast cancer (BC), with ATP-induced cell death (AICD) attracting increasing attention due to its distinctive specificity and potential therapeutic applications., Methods: This study employed genomic methodologies to investigate the correlation between drug sensitivity and types of AICD in BC. Initially, data from TCGA were utilized to construct a prognostic model and classification system for AICD. Subsequently, a series of bioinformatics analyses assessed the prognostic and clinical significance of this model within the context of BC., Results: Analysis revealed a cohort of 18 genes associated with AICD, exhibiting prognostic relevance. Survival analyses indicated that overall survival rates were significantly lower in high-risk populations compared to their low-risk counterparts. Furthermore, prognostic indicators linked to AICD demonstrated high accuracy in predicting survival outcomes in BC. Immunological assessments indicated heightened expression of anti-tumor infiltrating immune cells and immune checkpoint molecules in low-risk populations, correlating with various anti-tumor immune functions. Ultimately, a comprehensive prognostic model related to AICD was developed through univariate analysis, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. As Adenosine triphosphate (ATP) concentration increased, the viability of BC cells exhibited a general decline at each time point. Notably, ATP diminished the mitochondrial membrane potential in BC cells while enhancing it in normal breast epithelial cells. Additionally, ATP inhibited the migration of BC cells and promoted their apoptosis. ATP also stimulated reactive oxygen species (ROS) production in MCF-10A cells, with implications for the immune response in BC cells. Compared to the control group, expression levels of CLIC6 , SLC1A1 , and CEMIP were significantly reduced in the ATP intervention group, whereas ANO6 expression was elevated. ANO6 , CEMIP , and CLIC6 share genetic variants with BC, while SLC1A1 does not exhibit genetic causal variation with the disease., Conclusion: A valuable prognostic model associated with AICD has been established, capable of accurately predicting BC prognosis. The induction of cell death by ATP appears to play a protective role in BC progression. These findings carry significant implications for the implementation of personalized and tailored treatment strategies for BC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Zhang, Zhang, Sandai, Lu, Zhang and Wu.)

Immunotherapy stands as the frontrunner in treatment strategies imparting efficient remission in various types of cancer. In fact, emerging breakthroughs with immune checkpoint inhibitors (ICI) in a spectrum of cancers have evoked interest in research related to the potential effects of immunotherapy in breast cancer patients. A major challenge with breast cancer is the molecular heterogeneity that limits the efficacy of many therapeutic regimes. Clinical trials have shown favorable clinical outcomes with immunotherapeutic options in some subtypes of breast cancer. However, ICI monotherapy may not be sufficient for all breast cancer patients, emphasizing the need for combinatorial approaches. Ongoing research is focused on untangling the interplay of ICI with established as well as novel anticancer therapeutic regimens in preclinical models of breast cancer. Our review will analyze the existing research regarding the mechanisms and clinical impact of immunotherapy for the treatment of breast cancer. We shall evaluate the role of immune cell modulation for improved therapeutic response in breast cancer patients. This review will provide collated evidences about the current clinical trials that are testing out the implications of immunotherapy in conjunction with traditional treatment modalities in breast cancer and summarize the potential future research directions in the field. In addition, we shall underline the recent findings related to microbiota modulation as a key regulator of immune therapy response in cancer patients and its plausible applications in breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nandi and Sharma.)

Breast cancer is the most common and lethal malignancy among women worldwide. Cuproptosis, a newly identified copper-dependent cell death, is closely associated with cancer development. However, its regulatory mechanisms in breast cancer are not well studied. This study aims to establish a prognostic model for breast cancer to improve risk stratification. The mRNA expression data was downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering identified patterns based on cuproptosis-related genes. Key genes were screened using Weighted Gene Co-Expression Network Analysis and differentially expressed gene analysis. A prognostic model was constructed using Cox regression and evaluated with time-dependent receiver operating characteristic and Kaplan-Meier analyses. Functional pathways, immune cell infiltration, and other tumor characteristics were also analyzed. Two distinct cuproptosis patterns were identified. The top 21 differentially expressed genes, significantly associated with survival, were used to construct the prognostic model. The risk score has a negative correlation with survival. Enrichment analysis showed immune-related pathways enriched in the low-risk group, which also had more immune cell infiltration, higher stromal component, lower tumor purity, and lower tumor heterogeneity. Finally, significant differences of half maximal inhibitory concentration were also observed between patients in high- and low-risk groups who received chemotherapy and targeted therapy drugs. These findings in our study may provide evidence for further research and individualized management of breast cancer., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/aim: Macrophage-mediated cancer immune evasion is modulated by the balance between "the cluster of differentiation 47 (CD47), an anti-phagocytic signal" and "calreticulin (CALR), a pro-phagocytic signal". CD47 is highly expressed in various types of cancer. However, the expression profiles of CD47 and CALR in breast cancer, especially in different hormone receptor subtypes, and the effects of CD47 blockade in macrophage-mediated therapy are not well understood., Materials and Methods: The expression levels of CD47 and CALR were investigated in breast cancer and adjacent normal tissues using immunohistochemistry. To study the effects of CD47 blockade therapy, CD47 and CALR expression in breast cancer cell lines were determined. In vitro macrophage-mediated phagocytosis of breast cancer upon treatment with a monoclonal CD47 antibody (B6H12) were performed., Results: CD47 and CALR were overexpressed in breast cancer tissues and their up-regulation was associated with hormone receptor subtypes. Patients with Luminal A breast cancer had higher levels of CD47, while patients with triple-negative breast cancer (TNBC) had higher levels of CALR. The levels of CD47 and CALR were also elevated in breast cancer cell lines of Luminal A (MCF-7) and TNBC (MDA-MB-231) subtypes. Interestingly, the expression ratio of surface CD47/CALR was significantly higher in MCF-7. Moreover, in vitro phagocytosis assays revealed that blockage of CD47 enhanced macrophage-mediated activity in both cancer cells with dramatically higher degrees of phagocytosis in MCF-7., Conclusion: The expression profiles of CD47 and CALR in breast cancer subtypes and the benefit of CD47 blocking-based immunotherapy are herein provided., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Dose-dense chemotherapy is recommended for patients with breast cancer who have a high recurrence risk. However, whether dose-dense neoadjuvant chemotherapy (ddNAC) improves patient prognoses compared to the normal-dose regimen remains controversial. In this study, we evaluated the predictive value of immune activities on short-term outcomes for patients treated with ddNAC., Patients and Methods: We classified 82 patients with human epidermal growth factor receptor 2-negative breast cancer treated with NAC into a normal dose group (62 patients) and ddNAC group (20 patients) and examined the differences in clinicopathological features. The ddNAC group was further divided according to patient responses to NAC and the predictive factors for pathological complete response (pCR) were evaluated., Results: There were no differences in the clinicopathological features before NAC between the normal dose and ddNAC groups. Although the pCR rates tended to be higher in the ddNAC group compared than those in the normal dose group (35.0% vs. 25.8%), there was not significant difference (p=0.264). Among all patients treated with ddNAC, the absolute lymphocyte count decreased and the neutrophil-to-lymphocyte ratio increased during dose-dense doxorubicin plus cyclophosphamide treatment. There was no significant correlation between the pCR and any of the clinicopathological parameters tested including systemic peripheral markers and tumor-infiltrating lymphocyte levels., Conclusion: ddNAC affected the levels of systemic peripheral immune markers. However, monitoring these markers may not be useful for predicting responses to ddNAC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Accurate assessment of HER2 expression levels is paramount for determining eligibility for targeted therapies. HER2 immunohistochemistry provides a semiquantitative measurement of HER2 protein overexpression. Historically, little focus has been on the lower end of the HER2 expression range. The advent of novel therapeutic molecules that require fewer membrane epitopes to be effective has prompted a reevaluation of the current immunohistochemistry testing protocols, with special emphasis on the detection limit. Here, we have used Boston Cell Standards technology to determine the sensitivity of 2 commercially available HER2 immunohistochemistry assays, including a lower limit of detection., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The impact of tumor-infiltrating B cells on breast cancer (BRCA) outcomes remains poorly understood. Recent findings from Yang et al. identify an atypical, clonally expanded population of activated Fc receptor-like 4 (FCRL4) + B cells that is associated with improved overall survival in patients affected by various tumor types, including BRCA., Competing Interests: Declaration of interests L.G. is holding/has held research contracts with Lytix Biopharma, Promontory, and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, AbbVie, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The impact of aging on the immune landscape of luminal breast cancer (Lum-BC) is poorly characterized. Understanding the age-related dynamics of immune editing in Lum-BC is anticipated to improve the therapeutic benefit of immunotherapy in older patients. To this end, here we applied the 'multiple iterative labeling by antibody neo-deposition' (MILAN) technique, a spatially resolved single-cell multiplex immunohistochemistry method. We created tissue microarrays by sampling both the tumor center and invasive front of luminal breast tumors collected from a cohort of treatment-naïve patients enrolled in the prospective monocentric IMAGE (IMmune system and AGEing) study. Patients were subdivided into three nonoverlapping age categories (35-45 = 'young', n = 12; 55-65 = 'middle', n = 15; ≥70 = 'old', n = 26). Additionally, depending on localization and amount of cytotoxic T lymphocytes, the tumor immune types 'desert' (n = 22), 'excluded' (n = 19), and 'inflamed' (n = 12) were identified. For the MILAN technique we used 58 markers comprising phenotypic and functional markers allowing in-depth characterization of T and B lymphocytes (T&B-lym). These were compared between age groups and tumor immune types using Wilcoxon's test and Pearson's correlation. Cytometric analysis revealed a decline of the immune cell compartment with aging. T&B-lym were numerically less abundant in tumors from middle-aged and old compared to young patients, regardless of the geographical tumor zone. Likewise, desert-type tumors showed the smallest immune-cell compartment and were not represented in the group of young patients. Analysis of immune checkpoint molecules revealed a heterogeneous geographical pattern of expression, indicating higher numbers of PD-L1 and OX40-positive T&B-lym in young compared to old patients. Despite the numerical decline of immune infiltration, old patients retained higher expression levels of OX40 in T helper cells located near cancer cells, compared to middle-aged and young patients. Aging is associated with important numerical and functional changes of the immune landscape in Lum-BC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

This review focuses on the immune checkpoint inhibitors (ICIs) in the context of breast cancer (BC) management. These innovative treatments, by targeting proteins expressed on both tumor and immune cells, aim to overcome tumor-induced immune suppression and reactivate the immune system. The potential of this approach is the subject of numerous clinical studies. Here, we explore the key studies and emerging therapies related to ICIs providing a detailed analysis of their specific and combined use in BC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Gamma delta T cells (γδT cells) play crucial roles in the immune response against tumors, yet their functional dynamics under different cancer therapies remain poorly understood. Laser Ablative Immunotherapy (LAIT) is a novel cancer treatment modality combining local photothermal therapy (PTT) and intratumoral injection of an immunostimulant, N-dihydrogalactochitosan (glycated chitosan, GC). LAIT has been shown to induce systemic antitumor immune responses in pre-clinical studies and clinical trials, eradicating both treated local tumors and untreated distant metastases. In this study, we used LAIT to treat breast tumors in a mouse model and investigated the effects of LAIT on tumor-infiltrating γδT cells using single-cell RNA sequencing (scRNAseq). We characterized the γδT cells from tumors in control, PTT, GC, and LAIT (PTT + GC) groups, by identifying six distinct subtypes: activated, cytotoxic, cycling cytotoxic, IFN-enriched, antigen-presenting, and IL17-producing γδT cells. Differential gene expression analysis revealed that LAIT significantly upregulated genes associated with T cell activation, leukocyte adhesion, and interferon signaling in treated tumor tissues while downregulating genes involved in protein folding and stress responses. LAIT also uniquely increased the proportion of IL17-producing γδT cells, which correlated with prolonged survival in breast cancer patients, as analyzed using TCGA data. Furthermore, the transcriptomic profiles of γδT cells in LAIT-treated tumors closely resembled those in immune checkpoint inhibitor (ICI)-treated patients, suggesting potential synergistic effects. Our findings indicate that LAIT modulates the γδT cell transcriptome, enhancing their antitumor capabilities and providing a basis for combining LAIT with ICI therapy to improve cancer treatment outcomes., Competing Interests: Declaration of competing interest Wei R. Chen is co-founder and an unpaid member of the Board of Directors of Immunophotonics, Inc. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The most promising method of containing the COVID-19 pandemic is considered to be vaccination against SARS-CoV-2 infection. However, research on the relationship between vaccination against COVID-19 and cancer has primarily examined induced immunity rather than the disease itself. Considering that breast cancer is the most common cancer among women, the main goal of this study was to examine the impact of the Sinopharm and AstraZeneca vaccination on tumor characteristics such as tumor size, important tumor markers, tumor-infiltrating lymphocytes, metastasis to vital organs, and investigation of the PI3K/AKT signaling pathway, and the expression levels of relevant genes (PTEN, mTOR, AKT, PI3K, GSK3, and FoxO1) of the luminal B (MC4L2) mouse model. The tumor size of the mice was measured and monitored every two days, and after thirty days, the mice were euthanized. Remarkably, after vaccination, all vaccinated mice showed a decrease in the size of their tumor and an increase in the number of lymphocytes that had invaded the tumors. Tumor marker levels (VEGF, Ki-67, MMP-2/9), CD4/CD8 ratio, metastasis to vital organs, hormone receptors (ER, PR, and HER-2), and expression of genes related to the advancement of the PI3K/AKT signaling pathway were lower in vaccinated mice. Our research showed that the COVID-19 vaccine can have an anti-cancer effect by slowing the tumor progression and metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ductal carcinoma in situ and invasive ductal carcinoma represent two stages of breast cancer progression. A multitude of studies have shown that genomic instability increases during tumor development, as manifested by higher mutation and copy number variation rates. The advent of single-cell and spatial transcriptomics has enabled the investigation of the subtle differences in cellular states during the tumor progression at single-cell level, thereby providing more nuanced understanding of the intercellular interactions within the solid tumor. However, the evolutionary trajectory of tumor cells and the establishment of the immunosuppressive microenvironment during breast cancer progression remain unclear. In this study, we performed an exploratory analysis of the single-cell sequencing dataset of 13 ductal carcinoma in situ and invasive ductal carcinoma samples. We revealed that tumor cells became more malignant and aggressive during their progression, and T cells transited to an exhausted state. The tumor cells expressed various coinhibitory ligands that interacted with the receptors of immune cells to create an immunosuppressive tumor microenvironment. Furthermore, spatial transcriptomics data confirmed the spatial colocalization of tumor and immune cells, as well as the expression of the coinhibitory ligand-receptor pairs. Our analysis provides insights into the cellular and molecular mechanism underlying the formation of the immunosuppressive landscape during two typical stages of breast cancer progression., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Breast cancer is a complex disease with significant phenotypic heterogeneity of cells, even within a single breast tumor. Emerging evidence underscores the significance of intratumoral competition, which can serve as a key contributor to cancer drug resistance, imparting substantial clinical implications. Understanding the competitive dynamics is paramount as it can significantly influence disease progression and treatment outcomes. In the present work, a mathematical model was developed using a system of differential equations to describe the dynamic interactions between two cancer subtypes (each further classified into cancer stem cells and tumor cells) and innate immune cells. The purpose of the model is to comprehensively understand the competitive interactions between the heterogeneous subpopulations. The equilibrium points and stability analysis for each equilibrium point were established. Model simulations showed that the competition between two cancer subtypes directly affects the number of both species. When competition between two cancer subtypes is strong, increasing the immune response rate specific to the more competitive species effectively reduces the tumor size. However, if the competition is relatively weak, an optimal immune response rate is required to minimize the total number of tumor cells. Rates below the optimal level fail to reduce the population of the stronger species, whereas rates above the optimal level can lead to the recurrence of the weaker species. Overall, this model provides insights into breast cancer dynamics and guides the development of effective treatment strategies.

Surgical resection is the primary treatment approach for patients with breast cancer. Despite optimal multimodal treatment, metastatic recurrence remains a risk. Surgery-mediated systemic inflammation and local tissue inflammation generate an immunosuppressive and wound-healing environment that may accelerate cancer recurrence and metastasis post-operatively. Investigating the impact of surgery on local and systemic inflammation may provide knowledge for improvement of patient prognosis and treatment opportunities. Systemic cytokines were quantified in the blood plasma of patients with breast cancer pre-operatively, early post-operatively, and late post-operatively. Early post-operative levels of IL-6 were significantly elevated in patients who underwent mastectomy compared with wide local excision. Post-operative IL-6 levels correlate with clinicopathological features (age and BMI). The transcriptomes of local matched tumour and normal tumour adjacent (normal) breast tissue, from patients with breast cancer, were analysed by RNA-Seq. Elevated gene expressions of IL6, ADIPOQ, FABP4, LPL, PPARG, and CD36 in normal tissue were associated with worse overall survival of patients with ER-positive breast cancer. In tissue with higher expression of IL6 and ADIPOQ, a higher abundance of M2-like macrophage gene expression was identified. This study revealed perioperative systemic dynamics of inflammatory mediators and identified local immune-adipose-metabolism gene expression in tumour-adjacent tissue associated with pro-tumour function., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Background and Purpose: Local radiotherapy (RT) exerts immunostimulatory effects by inducing immunogenic cell death. However, it remains unknown whether in vitro-irradiated tumor cells can elicit anti-tumor responses and enhance the efficacy of local RT and immune checkpoint inhibitors when injected in vivo., Methods and Materials: We tested the "in vitro-irradiated cancer vaccine (ICV)", wherein tumor cells killed by varying doses of irradiation and their supernatants are intravenously injected. We examined the efficacy of combining local RT (24 Gy in three fractions), PD-L1 blockade, and the ICV in a murine breast cancer model. The immune cell profiles were analyzed via flow cytometry and immunohistochemistry. The cytokine levels were measured by multiplex immunoassays., Results: The ICV significantly increased the effector memory phenotype and interferon-γ production capacity in splenic CD8 + T cells. The in vitro-irradiated products contained immune response-related molecules. When combined with local RT and PD-L1 blockade, the ICV significantly delayed the growth of irradiated and non-irradiated tumors. The triple combination therapy increased the proportions of CD8 + T cells and effector memory CD8 + T cells while decreasing the proportion of CTLA-4 + exhausted CD8 + T cells within tumor microenvironment. Additionally, plasma level of interferon-γ and proliferation of effector T cells in the spleen and tumor-draining lymph nodes were significantly increased by the triple combination therapy., Conclusions: The ICV enhanced the therapeutic efficacy of local RT and PD-L1 blockade by augmenting anti-tumor immune responses. Our findings suggest a therapeutic potential of in vitro-irradiation products of tumor cells., Competing Interests: Declaration of competing interest Se Yup Lee has the patent related to the work in this study. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To assess the association between tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) samples and disease recurrence., Methods: This retrospective cohort study included women aged 18 years and older who underwent treatment between January 2007 and December 2020. Male patients, individuals diagnosed with invasive or microinvasive disease based on anatomopathological examination of surgical specimens, and those with a personal history of any other cancers were excluded. Additionally, the presence of "touching TILs" (lymphocytes in direct contact with tumor cells) and periductal desmoplasia were evaluated as complementary methods to represent the immunological microenvironment. The primary outcome was relapse-free survival based on TIL quantification adjusted for potential confounders. Pathologists assessed TILs in the sample with the highest tumor representation and quantified them as a percentage. Survival was evaluated using Kaplan‒Meier curves, log-rank tests, and Cox regression models., Results: A total of 191 patients met the eligibility criteria. The mean follow-up duration was 77.2 months, with a recurrence rate of 9.2%. Patients with TILs ≥ 17% had a greater risk of recurrence (HR 2.97, 95% CI 1.17-7.51; p = 0.02). Additionally, focal necrosis (HR 6.4, 95% CI 1.39-34.71; p = 0.018) or comedonecrosis (HR 4.53, 95% CI 1.34-15.28; p = 0.015) were associated with increased recurrence risk. According to the multivariate model, comedonecrosis and TILs ≥ 17% were significantly associated with recurrence (p = 0.034 and p = 0.035, respectively). Regarding the evaluations of "touching TILs" and periductal desmoplasia, no statistical significance was found when assessing their association with disease recurrence., Conclusion: In our cohort, a high percentage of TILs (≥ 17%) and the presence of comedonecrosis were independently associated with DCIS recurrence., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Breast cancer, a prevalent disease with significant mortality rates, often presents treatment challenges due to its complex genetic makeup. This review explores the potential of combining Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene knockout strategies with immunotherapeutic approaches to enhance breast cancer treatment. The CRISPR/Cas9 system, renowned for its precision in inducing genetic alterations, can target and eliminate specific cancer cells, thereby minimizing off-target effects. Concurrently, immunotherapy, which leverages the immune system's power to combat cancer, has shown promise in treating breast cancer. By integrating these two strategies, we can potentially augment the effectiveness of immunotherapies by knocking out genes that enable cancer cells to evade the immune system. However, safety considerations, such as off-target effects and immune responses, necessitate careful evaluation. Current research endeavors aim to optimize these strategies and ascertain the most effective methods to stimulate the immune response. This review provides novel insights into the integration of CRISPR/Cas9-mediated knockout strategies and immunotherapy, a promising avenue that could revolutionize breast cancer treatment as our understanding of the immune system's interplay with cancer deepens., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemotherapy is the cornerstone of triple-negative breast cancer. The poor effectiveness and severe neuropathic pain caused by it have a significant impact on the immune system. Studies confirmed that immune cells in the tumor microenvironment (TME), have critical roles in tumor immune regulation and prognosis. In this study, it is revealed that the painless administration of Esketamine, combined with Cisplatin (DDP), can exert an anti-tumor effect, which is further boosted by the hydrogel delivery system. It is also discovered that Esketamine combined with DDP co-loaded in Poloxamer Hydrogel (PDEH) induces local immunity by increasing mature Dendritic Cells (mDCs) and activated T cells in PDEH group while the regulatory T cells (Tregs) known as CD4 + CD25 + FoxP3 + decreased significantly. Finally, , CD8 + and CD4 + T cells in the spleen exhibited a significant increase, suggesting a lasting immune impact of PDEH. This study proposes that Esketamine can serve as a painless immune modulator, enhancing an anti-tumor effect while co-loaded in poloxamer hydrogel with DDP. Along with improving immune cells in the microenvironment, it can potentially alleviate anxiety and depression. With its outstanding bio-safety profile, it offers promising new possibilities for painless clinical therapy., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance 2 years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation., Patients and Methods: Women with stage I-III hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance [European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 ≥40/100] 2 years after diagnosis (year 2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers [interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, interferon γ, IL-1 receptor antagonist, tumor necrosis factor-α, and C-reactive protein], and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling., Results: Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year 2. High pre-treatment levels of IL-6 (quartile 4 versus 1) were associated with global CRF at year 2 [adjusted odds ratio (aOR): 2.06 (95% confidence interval [CI] 1.40-3.03); P = 0.0002; area under the receiver operating characteristic curve = 0.74]. Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese [62.4%; mean body mass index 28.0 (standard deviation 6.3 kg/m 2 )] and physically inactive (53.5% did not meet World Health Organization recommendations). Clinical and behavioral associations with CRF at year 2 included pre-treatment CRF [aOR versus no pre-treatment CRF: 3.99 (95% CI 2.81-5.66)], younger age [aOR per 1-year decrement: 1.02 (95% CI 1.01-1.03)], current tobacco smoking [aOR versus never: 1.81 (95% CI 1.26-2.58)], and worse insomnia or pain [aOR per 10-unit increment: 1.08 (95% CI 1.04-1.13), and 1.12 (95% CI 1.04-1.21), respectively]. Secondary analyses indicated additional associations of IL-2 [aOR per log-unit increment: 1.32 (95% CI 1.03-1.70)] and IL-10 [0.73 (95% CI 0.57-0.93)] with global CRF and of C-reactive protein [1.42 (95% CI 1.13-1.78)] with cognitive CRF at year 2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF., Conclusions: This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance 2 years later among a large prospective sample of survivors of breast cancer., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The immunosuppressive nature of the tumor microenvironment (TME) contributes to radioresistance, thereby impairing the effectiveness of radiotherapy as a therapeutic intervention. Activation through the stimulator of interferon genes (STING) pathway shows potential in modulating immunogenicity. However, the therapeutic efficacy of STING agonists might be restricted by off-target effects and potential cytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous microneedles were employed for precise delivery of the STING agonist MSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration enabled by microneedles, EXOs can be continually released and accumulate within deep residual tumors. Once internalized, these EXOs release the encapsulated MSA-2, facilitating the activation of the STING pathway upon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy elevates the type I interferon level, promotes dendric cell maturation, and modulates the immunosuppressive TME, showing efficient antitumor efficacy in both primary/metastatic tumors. Furthermore, the induction of a potent immune response effectively prevented tumor recurrence. The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

Background: Breast cancer (BRCA) represents a substantial global health challenge marked by inadequate early detection rates. The complex interplay between the tumor immune microenvironment and fatty acid metabolism in BRCA requires further investigation to elucidate the specific role of lipid metabolism in this disease., Methods: We systematically integrated nine machine learning algorithms into 184 unique combinations to develop a consensus model for lipid metabolism-related prognostic genes (LMPGS). Additionally, transcriptomics analysis provided a comprehensive understanding of this prognostic signature. Using the ESTIMATE method, we evaluated immune infiltration among different risk subgroups and assessed their responsiveness to immunotherapy. Tailored treatments were screened for specific risk subgroups. Finally, we verified the expression of key genes through in vitro experiments., Results: We identified 259 differentially expressed genes (DEGs) related to lipid metabolism through analysis of the cancer genome atlas program (TCGA) database. Subsequently, via univariate Cox regression analysis and C-index analysis, we developed an optimal machine learning algorithm to construct a 21-gene LMPGS model. We used optimal cutoff values to divide the lipid metabolism prognostic gene scores into two groups according to high and low scores. Our study revealed distinct biological functions and mutation landscapes between high-scoring and low-scoring patients. The low-scoring group presented a greater immune score, whereas the high-scoring group presented enhanced responses to both immunotherapy and chemotherapy drugs. Single-cell analysis highlighted significant upregulation of CPNE3 in epithelial cells. Moreover, by employing molecular docking, we identified niclosamide as a potential targeted therapeutic drug. Finally, our experiments demonstrated high expression of MTMR9 and CPNE3 in BRCA and their significant correlation with prognosis., Conclusion: By employing bioinformatics and diverse machine learning algorithms, we successfully identified genes associated with lipid metabolism in BRCA and uncovered potential therapeutic agents, thereby offering novel insights into the mechanisms and treatment strategies for BRCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Yi, Xie, Liu, Liu and Yan.)

The interplay between immune cells and malignant cells represents an essential chapter in the eradication of breast cancer. This widely distributed and diverse form of cancer represents a major threat to women worldwide. The incidence of breast cancer is related to several risk factors, notably genetic predisposition and family antecedents. Despite progress in treatment modalities varying from surgery and chemotherapy to radiotherapy and targeted therapies, persistently high rates of recurrence, metastasis, and treatment resistance underscore the urgent need for new therapeutic approaches. Immunotherapy has gained considerable ground in the treatment of breast cancer, as it takes advantage of the complex interactions within the tumor microenvironment. This dynamic interplay between immune and tumor cells has become a key point of focus in immunological research. This study investigates the role of various cancer markers, such as neoantigens and immune regulatory genes, in the diagnosis and treatment of breast tumors. Moreover, it explores the future potential of immune checkpoint inhibitors as therapeutically effective agents, as well as the challenges that prevent their efficacy, in particular tumor-induced immunosuppression and the difficulty of achieving tumor specificity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Naji, Ghouzlani, Rafii, Sadiqi, Kone, Harmak, Choukri, Kandoussi, Karkouri and Badou.)

Background: Natural killer (NK) cells play crucial roles in mediating anti-cancer activity in breast cancer (BRCA). However, the potential of NK cell-related molecules in predicting BRCA outcomes and guiding personalized therapy remains largely unexplored. This study focused on developing a prognostic and therapeutic prediction model for BRCA by incorporating NK cell-related genes., Methods: The data analyzed primarily originated from the TCGA and GEO databases. The prognostic role of NK cells was evaluated, and marker genes of NK cells were identified via single-cell analysis. Module genes closely associated with immunotherapy resistance were identified by bulk transcriptome-based weighted correlation network analysis (WGCNA). Following taking intersection and LASSO regression, NK-related genes (NKRGs) relevant to BRCA prognosis were screened, and the NK-related prognostic signature was subsequently constructed. Analyses were further expanded to clinicopathological relevance, GSEA, tumor microenvironment (TME) analysis, immune function, immunotherapy responsiveness, and chemotherapeutics. Key NKRGs were screened by machine learning and validated by spatial transcriptomics (ST) and immunohistochemistry (IHC)., Results: Tumor-infiltrating NK cells are a favorable prognostic factor in BRCA. By combining scRNA-seq and bulk transcriptomic analyses, we identified 7 NK-related prognostic NKRGs (CCL5, EFHD2, KLRB1, C1S, SOCS3, IRF1, and CCND2) and developed an NK-related risk scoring (NKRS) system. The prognostic reliability of NKRS was verified through survival and clinical relevance analyses across multiple cohorts. NKRS also demonstrated robust predictive power in various aspects, including TME landscape, immune functions, immunotherapy responses, and chemotherapeutic sensitivity. Additionally, KLRB1 and CCND2 emerged as key prognostic NKRGs identified through machine learning and external validation, with their expression correlation with NK cells confirmed in BRCA specimens by ST and IHC., Conclusions: We developed a novel NK-related gene signature that has proven valuable for evaluating prognosis and treatment response in BRCA, expecting to advance precision medicine of BRCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hou, Li, Chong, Yin, Guo, Yang, Li and Yin.)

Background: Breast cancer is a significant public health issue worldwide, being the most prevalent cancer among women and a leading cause of death related to this disease. The molecular processes that propel breast cancer progression are not fully elucidated, highlighting the intricate nature of the underlying biology and its crucial impact on global health. The objective of this research was to perform bioinformatics analyses on breast cancer-related datasets to gain a comprehensive understanding of the molecular mechanisms at play and to identify key genes associated with the disease., Methods: The toolkit analyses involve techniques such as differential gene expression analysis, Gene Set Enrichment Analysis (GSEA), Weighted Co-Expression Network Analysis (WGCNA), and Machine Learning algorithms. Furthermore, in vitro cell experiments have demonstrated the impact of HSPB6 on cell migration, proliferation, and apoptosis., Results: The study identified multiple genes that displayed differential expression in breast cancer, notably FHL1 and HSPB6. A machine learning model was developed in this study and specifically trained for breast cancer diagnosis using these genes, achieving high precision. Furthermore, analysis of immune cell infiltration revealed an enrichment of Tregs and M2 macrophages in the treated group, showcasing its significant impact on the tumor's immunological context. A temporal analysis of breast cancer cells using single-cell RNA sequencing provided insights into cellular developmental trajectories and highlighted changes in expression patterns across key genes during disease progression. The upregulation of HSPB6 in MCF7 cells significantly inhibited both cell migration and proliferation abilities, suggesting that promoting HSPB6 expression could induce ferroptosis in breast cancer cells., Conclusion: Our findings have identified compelling molecular targets and distinctive diagnostic markers for the clinical management of breast cancer. This data will serve as crucial guidance for further research in the field., (© 2024. The Author(s).)

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) and the percentage of tumor-infiltrating lymphocytes (TILs) are established prognostic biomarkers in early breast cancer (BC). While exercise training is effective as supportive care throughout the BC journey, its impact on the efficacy of NAC is unknown. This study aims to investigate the influence of a supervised exercise training program (SETP) on pCR and TILs in BC women undergoing NAC., Methods: Retrospective exploratory analysis of the subgroup of BC patients treated with NAC included in a clinical trial randomizing to STEP and control arm. Endpoints were pCR, biopsy, and stromal TILs., Results: Sixty-four participants were included, with a mean age of 50.3 ± 10.1 years, predominantly stage II and III disease (n = 58, 90.6%), HER2 + (n = 23, 35.9%), or triple-negative (n = 19, 29.7%) tumors. pCR was achieved in 56.7% and 55.9% in the STEP and control arm (p = 0.950). In the STEP arm, median TILs were 5.0 (0.0-80.0) and 5.0 (5.0-30.0), while in the control arm, 5.0 (0.0-90.0) and 0.0 (0.0-30.0) for biopsy and tumor site, respectively. The difference in TILs between arms was 0.04 (confidence interval (CI 95%) - 13.6, 13.7; p = 0.995) and - 4.3 (CI 95% - 11.5, 2.9; (p = 0.233) for biopsy and tumor site, respectively. No statistically significant difference was discerned between the groups concerning TILs of the biopsy. However, a marginally higher TIL level at the tumor site was associated with the SETP arm., Conclusions: No differences were discerned within and between groups on both pCR and TILs, in possible relation to the exploratory nature of the analysis. Future adequately powered research is warranted., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Breast cancer (BC) remains a significant health issue globally and most common cause of mortality in women. Enhancing our understanding on biomarkers may greatly improve both diagnostic and therapeutic approaches to this disease., Methods: We retrospectively assessed tumor samples from 228 BC cases and 51 normal samples, alongside relevant clinical data. Neuronal vesicle trafficking associated 2(NSG2) expression was evaluated through bioinformatics and multiplex immunohistochemistry. Associations between NSG2 expression, tumor-infiltrating immune cells (TIICs), immune checkpoints, and clinical outcomes were investigated., Results: NSG2 was present in both breast cancer cells and adjacent stromal cells. Increased NSG2 expression in cancer cells correlated with greater tumor size, distant metastasis, and more advanced clinical stages. Kaplan-Meier survival and multivariate analyses identified NSG2 expression in both cancer and stromal cells as an independent prognostic factor for breast cancer survival. Elevated NSG2 levels both in cancer and stroma cells were linked to increased CD4+ T, CD8+ T, and Lamp3+ dendritic cells infiltration in stromal regions ( P < 0.05). Conversely, the expression of NSG2 in the stroma was negatively correlated with CD20+ B cells ( P < 0.05). Additionally, NSG2 expression was found to be associated with CTLA-4 levels ( P < 0.05)., Conclusion: NSG2 seems to be a significant component of the BC immune microenvironment and may serve as an important prognostic marker., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Gu, Sun, Yang, Zhang, Lu and Ni.)

Chemokines bind to specific chemokine receptors, known as cell surface G protein-coupled receptors, constructing chemokine axes which lead to cell migration and invasion in developmental stage, pathophysiological process, and immune reactions. The chemokine axes in the tumor microenvironment are involved in tumor growth, angiogenesis, cancer stem-like cell properties, metastasis, and chemoresistance, modifying tumor immune contexture and cancer progression. Clinical features, including tumor state, grade, lymph node metastasis, and cancer subtypes, are related to the specific chemokine axes, which play a significant role in immune contexture and cell to cell interaction in the tumor microenvironment, followed by altered cancer prognosis and overall survival. The present review summarizes the role of chemokine axes in breast cancer, based on data obtained from cell line and animal models and human tumor samples. This review provides information that understand the important roles of each chemokine axis in breast cancer, probably offering a clue of adjuvant therapeutic options to improve the quality of life and survival for patients with breast cancer., (© 2024 The Author(s). Published by IMR Press.)

Background: As a novel cell death form, cuproptosis results from copper combining with lipidated proteins in the tricarboxylic acid cycle. To the best of our knowledge no study has yet comprehensively analyzed the relationship between cuproptosis-related genes and breast cancer., Methods: The expression, prognostic value, mutations, chemosensitivity, and immune infiltration of cuproptosis-related genes in breast carcinoma patients were analyzed, PPI networks were constructed, and enrichment analyses were performed based on these genes. TIMER, UALCAN, Kaplan-Meier plotter, Human Protein Atlas, cBioPortal, STRING, GeneMANIA, DAVID, and R program v4.0.3 were used to accomplish the analyses above., Results: Compared to normal breast tissues, FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, MTF1, and GLS were down-regulated in breast cancer tissues, while CDKN2A was up-regulated. High expression of FDX1, LIAS, DLD, DLAT, MTF1, GLS, and CDKN2A were associated with favorable overall survival. Cuproptosis-related genes showed a high alteration rate (51.3%) in breast cancer, contributing to worse clinical outcomes. The expression levels of FDX1, LIPT1, DLD, DLAT, PDHA1, PDHB, MTF1, GLS, and CDKN2A were associated positively with 1 or more immune cell infiltrations in breast cancer. Patients with high levels of B cell, CD4+ T cell, CD8+ T cell, and dendritic cell infiltration had a higher survival rate at 10 years., Conclusion: This study comprehensively investigated relationships between cuproptosis and breast cancer by bioinformatic analyses. We found that cuproptosis-related genes were generally lowly expressed in breast carcinoma tissue. As the critical gene of cuproptosis, high expression of FDX1 was related to favorable prognoses in breast cancer patients; thus, it might be a potential prognostic marker. Moreover, genes associated with cuproptosis were linked to immune infiltration in breast cancer and this relationship affected the prognosis of breast cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Breast cancer (BC) is 1 of the most common malignant tumors among women globally. This study aimed to develop a prognostic signature based on aggrephagy-related genes (ARGs). Transcriptomic and clinical data for BC patients were downloaded from the cancer genome atlas and GEO databases. Differential expression analysis, univariate Cox proportional hazards regression and least absolute shrinkage and selection operator Cox regression were employed to construct a prognostic signature. Consensus clustering, evaluation of immune infiltration and drug sensitivity, and gene set enrichment analysis, and development of nomogram were performed. The expression of ARGs was validated using data from the Cancer Cell Line Encyclopedia and clinical samples. Eleven ARGs were abnormally expressed in BC, with 5 showing significant correlations with BC prognosis. Consensus clustering identified 2 molecular subtypes with distinct prognoses. A prognostic signature including 5 ARGs (VIM, TUBB1, TUBA3E, TUBA3D, TUBA1C) was developed, which showed high performance in predicting BC prognosis. The low-risk group showed enrichment in extracellular matrix organization and cell migration processes while chromosome separation was suppressed. Additionally, patients in this group also show activation in several signaling pathways including MAPK, PI3K-AKT, and cAMP pathways, whereas cell cycle and neutrophil extracellular trap formation were significantly inhibited. The signature was also associated with immune infiltration and drug sensitivity. A nomogram incorporating the risk signature, clinical stage and chemotherapy was constructed, demonstrating excellent performance in predicting prognosis. The expression of signature-related genes were validated in patients with BC. This study successfully constructed molecular subtypes and a prognostic signature based on ARGs in BC, and developed a nomogram., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Breast cancer is the most diagnosed malignancy and major cause of cancer death among women population in the worldwide. Ferroptosis is a recently discovered iron-dependent regulated cell death involved in tumor progression and therapeutic response. Moreover, increasing studies have implied that ferroptosis is a promising approach to eliminating cancer cells like developing iron nanoparticles as a therapeutic agent. However, resistance to ferroptosis is a vital distinctive hallmark of cancer. Therefore, further investigation of the mechanism of ferroptosis resistance to enhance its tumor sensitivity is essential for ferroptosis-target breast cancer therapy. Our results revealed that the activation of C5a/C5aR pathway can drive resistance to ferroptosis and reshaping breast cancer immune microenvironment. Accordingly, loading PEG-Fe 3 O 4 with C5aRA significantly improved the anti-tumor effect of PEG- Fe 3 O 4 by inhibiting ferroptosis resistance and increasing macrophage polarization toward M1 phenotype. Our findings presented a novel cancer therapy strategy that combined cancer cell metal metabolism regulation and immunotherapy. The study also provided support for further evaluation of PEG- Fe 3 O 4 @C5aRA as a novel therapeutic strategy for breast cancer in clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Li, Zhang, Zhao, Zhao, Wu, Sun, Song, Zou, Zou, Han, Deng, Wang, Rao, Xu, Wang, Guo, Ding, Shi, Wu and Chen.)

Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of neural cell adhesion molecule 1 (NCAM1) + alpha-smooth muscle actin (αSMA) + CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1 + αSMA + CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1 + αSMA + CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy., (© 2024. The Author(s).)

Background: Breast cancer remains a significant global health challenge. Understanding its etiological factors, particularly the role of immune system components, is crucial. This study leverages Mendelian randomization (MR) to investigate the causal relationship between various immune cell features and the risk of developing breast cancer., Methods: Utilizing two-sample MR analysis, we examined 731 immune cell features across 7 groups for their potential causal links to breast cancer. We analyzed genome-wide association studies (GWAS) data of 257,730 Europeans, comprising 17,389 cases and 240,341 controls, focusing on 24,133,589 single nucleotide polymorphisms (SNPs). Instrumental variables (IVs) were selected based on genetic associations, with rigorous statistical methods employed, including inverse variance weighting (IVW) and weighted median-based estimation., Results: Our analysis identified 20 immunophenotypes with significant causal associations with breast cancer risk. Notably, contain B cell, mature T cell, T + B + NK (TBNK) cells, regulatory T (Treg) cell, Classic dendritic cells (cDCs), Monocyte, and Myeloid cell group features displayed positive or negative correlations with breast cancer. For instance, specific B cell phenotypes were found to have both positive and negative causal relationships with breast cancer. Additionally, reverse MR analysis revealed no significant causal effects of breast cancer on these immune characteristics., Conclusions: This study underscores the complex interplay between various immune cell phenotypes and breast cancer risk. The identified immunophenotypes could be potential biomarkers or targets for future therapeutic interventions. Our findings contribute to a deeper understanding of the immunological dimensions of breast cancer etiology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Breast cancer has the highest mortality rate among all cancers affecting females worldwide. Several new effective therapeutic strategies are being developed to minimize the number of breast cancer-related deaths and improve the quality of life of breast cancer patients. However, resistance to conventional therapies in breast cancer patients remains a challenge which could be due to several reasons, including changes in the tumor microenvironment. Attention is being diverted towards minimizing the resistance, toxicity, and improving the affordability of therapeutics for better breast cancer management. This includes personalized medicine, target-specific drug delivery systems, combinational therapies and artificial intelligence based screening and disease prediction. Nowadays, researchers and clinicians are also exploring the use of combinatorial immunotherapies in breast cancer patients, which have shown encouraging results in terms of improved survival outcomes. This study attempts to analyze the role of combinational immunotherapies in breast cancer patients, and offer insights into their effectiveness in breast cancer management., Methodology: We conducted a systematic review and meta-analysis for which we selected the randomized clinical trials (RCTs) focused on completed Phase I/II/III/IV clinical trials investigating combination immunotherapies for breast cancer. The analysis aimed to assess the efficacy of combination therapies in comparison to mono-therapies, focusing on overall survival (OS), and progression-free survival (PFS)., Results: We observed that, combination immunotherapies significantly (P<0.05) improved OS as compared to single-drug therapies in the Phase I with overall Risk ratio (RR) of 16.17 (CI 2.23,117.50), Phase II with an overall RR of 19.19 (CI 11.76,31.30) and for phase III overall RR 22.27 (CI 13.60,36.37). In the case of PFS, it was significant with RR: 12.35 (CI 2.14, 71.26) in Phase I RR 6.10 (CI 4.31, 8.64) in phase II, RR 8.95 (CI 6.09, 13.16) in phase III and RR 14.82 (CI 6.49, 33.82) in Phase IV of clinical trials., Conclusion: The observed improvements in overall survival and progression-free survival suggest that combination immunotherapies could serve as a better approach to breast cancer management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sisodiya, Kasherwal, Rani, Mishra, Kumar, Khan, Aftab, Shagufta, Singh, Gupta, Tanwar and Hussain.)