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The tumor microenvironment (TME) constitutes a complex microenvironment comprising a diverse array of immune cells and stromal components. Within this intricate context, tumor-associated macrophages (TAMs) exhibit notable spatial heterogeneity. This heterogeneity contributes to various facets of tumor behavior, including immune response modulation, angiogenesis, tissue remodeling, and metastatic potential. This review summarizes the spatial distribution of macrophages in both the physiological environment and the TME. Moreover, this paper explores the intricate interactions between TAMs and diverse immune cell populations (T cells, dendritic cells, neutrophils, natural killer cells, and other immune cells) within the TME. These bidirectional exchanges form a complex network of immune interactions that influence tumor immune surveillance and evasion strategies. Investigating TAM heterogeneity and its intricate interactions with different immune cell populations offers potential avenues for therapeutic interventions. Additionally, this paper discusses therapeutic strategies targeting macrophages, aiming to uncover novel approaches for immunotherapy. EjPgUqH7NocL1u9xj7Aojm Video Abstract [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, represented by immune checkpoint blocking and chimeric antigen receptor (CAR) T cell therapy, has achieved promising results in clinical applications. However, it faces challenges that hinder its further development, such as limited response rates and poor tumor permeability. The efficiency of tumor immunotherapy is also closely linked to the structure and function of the immune microenvironment where the tumor resides. Recently, nanoparticle‐based tumor immune microenvironment (TIME) modulation strategies have attracted a great deal of attention in cancer immunotherapy. This is primarily due to the distinctive physical characteristics of nanoparticles, which enable them to effectively infiltrate the TIME and selectively modulate its key constituents. This paper reviews recent advances in nanoparticle engineering to improve anti‐cancer immunotherapy. Emerging nanoparticle‐based approaches for modulating immune cells, tumor stroma, cytokines and immune checkpoints are discussed, aiming to overcome current challenges in the clinic. In addition, integrating immunotherapy with various treatment modalities such as chemotherapy and photodynamic therapy can be facilitated through the utilization of nanoparticles, thereby enhancing the efficacy of cancer treatment. The future challenges and opportunities of using nanomaterials to reeducate the suppressive immune microenvironment of tumors are also discussed, with the aim of anticipating further advancements in this growing field. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR‐T cell therapy, many factors were found to be associated with the efficacy of CAR‐T therapy. This paper reviews the factors affecting the effect of CAR‐T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR‐T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies. [ABSTRACT FROM AUTHOR]

Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumour. Despite advancements in surgery, radiotherapy and chemotherapy, which have improved the prognosis of most patients, a subset of patients with poor prognoses still exist due to loss of surgical opportunities, postoperative recurrence, and metastasis, among other reasons. The tumour microenvironment (TME) is a complex organization composed of tumour, stromal, and endothelial cells. Communication and interaction between tumours and immune cells within the TME are increasingly being recognized as pivotal in inhibiting or promoting tumour development. Previous studies on T cells in the TME of HNSCC have yielded novel therapeutic possibilities. However, the function of B cells, another adaptive immune cell type, in the TME of HNSCC patients has yet to be determined. Recent studies have revealed various distinct subtypes of B cells and tertiary lymphoid structures (TLSs) in the TME of HNSCC patients, which are believed to impact the efficacy of immune checkpoint inhibitors (ICIs). Therefore, this paper focuses on B cells in the TME to explore potential directions for future immunotherapy for HNSCC. [ABSTRACT FROM AUTHOR]

Objective: This paper aimed to investigate the PI3K/Akt/mTOR signal-pathway regulator factor-related lncRNA signatures (PAM-SRFLncSigs), associated with regulators of the indicated signaling pathway in patients with lung adenocarcinoma (LUAD) undergoing immunotherapy. Materials and Methods: In this retrospective study, we employed univariate Cox, multivariate Cox, and least absolute shrinkage and selection operator (LASSO) regression analyses to identify prognostically relevant long non-coding RNAs (lncRNAs), construct prognostic models, and perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Subsequently, immunoassay and chemotherapy drug screening were conducted. Finally, the prognostic model was validated using the Imvigor210 cohort, and tumor stem cells were analyzed. Results: We identified seven prognosis-related lncRNAs (AC084757.3, AC010999.2, LINC02802, AC026979.2, AC024896.1, LINC00941 and LINC01312). We also developed prognostic models to predict survival in patients with LUAD. KEGG enrichment analysis confirmed association of LUAD with the PI3K/Akt/mTOR signaling pathway. In the analysis of immune function pathways, we discovered three good prognostic pathways (Cytolytic_activity, Inflammation-promoting, T_cell_co-inhibition) in LUAD. Additionally, we screened 73 oncology chemotherapy drugs using the "pRRophetic" algorithm. Conclusion: Identification of seven lncRNAs linked to regulators of the PI3K/Akt/mTOR signaling pathway provided valuable insights into predicting the prognosis of LUAD, understanding the immune microenvironment and optimizing immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Highly expressed azo-reductase (AZOR) selectively reduces Azo-DON to DON in hypoxic tumor environments, impair glutamine metabolism in cancer cells, and promote tumor cell death without affecting T cell metabolism and proliferation, thereby generating strong antitumor immune responses. CB-PLG nanoparticles (CBP) mentioned in the paper can enhance the degree of hypoxia in normoxic tumors, which is conducive to efficient reduction of Azo-DON at tumor sites. [Display omitted] • Azo-DON is a novel hypoxia-active prodrug of glutamine antagonist. • Azo-DON selectively blocks tumor glutamine metabolism after reducing to DON. • T cells continue to proliferate and remain active when Azo-DON is reduced to DON. • CBP nanoparticles increase tumor hypoxia and facilitate the reduction of Azo-DON. Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), have demonstrated remarkable anti-tumor effects by blocking tumor glutamine metabolism, but their use is frequently causing toxicity. Despite the existence of multiple glutamine antagonist prodrug designs, a tumor-selective prodrug has yet to be developed. Herein, a novel prodrug of DON, Azo-DON, has been developed, which remains stable and inactive in normal tissues with sufficient oxygen levels, while can be selectively reduced to DON by highly expressed azo-reductase in hypoxic tumor environments. This leads to blockade of glutamine metabolism in cancer cells and promotes cell death without affecting T cell proliferation. In a high-hypoxic H22 hepatoma cancer model, Azo-DON showed a 1.8-fold enhancement in glutamine blockade compared to the control group, resulting in a tumor suppression rate (TSR) of 84.2% in vivo with no significant weight loss. In a low-hypoxic CT26 colon cancer model, when combined with vascular disrupting agent nanoparticles (CBP) to induce a hypoxic environment, Azo-DON exhibited a 4.6-fold enhancement in glutamine blockade over the control group, resulted in a remarkable TSR of 96.6% in vivo. This innovative approach represents a promising strategy for the application of broad-spectrum metabolic inhibitors in the field of precision cancer treatment. [ABSTRACT FROM AUTHOR]