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The research and development of messenger RNA (mRNA) cancer vaccines have gradually overcome numerous challenges through the application of personalized cancer antigens, structural optimization of mRNA, and the development of alternative RNA-based vectors and efficient targeted delivery vectors. Clinical trials are currently underway for various cancer vaccines that encode tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), or immunomodulators. In this paper, we summarize the optimization of mRNA and the emergence of RNA-based expression vectors in cancer vaccines. We begin by reviewing the advancement and utilization of state-of-the-art targeted lipid nanoparticles (LNPs), followed by presenting the primary classifications and clinical applications of mRNA cancer vaccines. Collectively, mRNA vaccines are emerging as a central focus in cancer immunotherapy, offering the potential to address multiple challenges in cancer treatment, either as standalone therapies or in combination with current cancer treatments.

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8 + T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8 + T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca 2+ -ATPase SERCA2, facilitating the mitochondrial Ca 2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca 2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca 2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8 + T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8 + T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.

Cancer vaccines have shown promise as effective means of antitumor immunotherapy by inducing tumor antigen-specific T cell immunity. In this study, a novel peptide-based tumor nanovaccine that boosts antigen presentation and elicits effective antitumor immunity is developed. The adjuvant characteristics of an antimicrobial peptide-derived core peptide, FK-13, are investigated and used it to generate a fusion peptide named FK-33 with tumor antigen epitopes. l-phenylalanine-based poly(ester amide) (Phe-PEA), 8p4, is also identified as a competent delivery vehicle for the fusion peptide FK-33. Notably, the vaccination of 8p4 + FK-33 nanoparticles (8FNs) in vivo induces dendritic cell activation in the lymph nodes and elicits robust tumor antigen-specific CD8 + T cell response. The nanovaccine 8FNs demonstrate significant therapeutic and prophylactic efficacy against in situ tumor growth, effectively inhibit tumor metastasis, and significantly prolong the survival of tumor-bearing mice. Moreover, 8FNs can incorporate different tumor antigens and exhibit a synergistic therapeutic effect with antiprogrammed cell death protein 1 (PD-1) therapy. In summary, 8FNs represent a promising platform for personalized cancer vaccines and may serve as a potential combinational modality to improve current immunotherapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Personalized immunotherapy targeting tumor-specific antigens (TSAs) could generate efficient and safe antitumor immune response without damaging normal tissues. Although neoantigen vaccines have shown therapeutic effect in clinic trials, precise prediction of neoantigens from tumor mutations is still challenging. The host antitumor immune response selects and activates T cells recognizing tumor antigens. Hence, T cells engineered with T-cell receptors (TCRs) from these naturally occurring tumor antigen-specific T (Tas) cells in a patient will target personal TSAs in his/her tumor. To establish such a personalized TCR-T cell therapy, we comprehensively characterized T cells in tumor and its adjacent tissues by single-cell mRNA sequencing (scRNA-seq), TCR sequencing (TCR-seq) and in vitro neoantigen stimulation. Compared to bystander T cells circulating among tissues, Tas cells were characterized by tumor enrichment, tumor-specific clonal expansion and neoantigen specificity. We found that CXCL13 is a unique marker for both CD4 + and CD8 + Tas cells. Importantly, TCR-T cells expressing TCRs from Tas cells showed significant therapeutic effects on autologous patient-derived xenograft (PDX) tumors. Intratumoral Tas cell levels measured by CXCL13 expression precisely predicted the response to immune checkpoint blockade, indicating a critical role of Tas cells in the antitumor immunity. We further identified CD200 and ENTPD1 as surface markers for CD4 + and CD8 + Tas cells respectively, which enabled the isolation of Tas cells from tumor by Fluorescence Activating Cell Sorter (FACS) sorting. Overall, our results suggest that TCR-T cells engineered with Tas TCRs are a promising agent for personalized immunotherapy, and intratumoral Tas cell levels determine the response to immunotherapy., (© 2022. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.)

Messenger RNA (mRNA)-based cancer vaccine has become a popular approach for developing personalized and effective antitumor immunotherapy. To achieve robust antitumor efficacy, mRNA-encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells for efficient antigen presentation; meanwhile, the vaccine would have adjuvant effect by stimulating innate immune response to boost the full activation of adaptive immunity. Recently, we reported a minimalist nanovaccine by formulating tumor antigen-encoding mRNA with a lipid-like material named C1, which could efficiently deliver mRNA into dendritic cells with simultaneous Toll-like receptor 4 (TLR4) stimulation, together induced T cell activation. Importantly, C1 mRNA nanovaccine exhibited significant antitumor efficacy on several tumor mouse models. Here, we discuss the nanovector-facilitated mRNA delivery and translation in dendritic cells, the self-adjuvant property of nanovectors, the challenges of personalized tumor antigen selection, and the potential strategies for developing efficacious mRNA cancer vaccines targeting the immunosuppressive tumor microenvironment.

Immunologic checkpoint blockade has been proven effective in a variety of malignancies. However, high rates of resistance have substantially hindered its clinical use. Understanding the underlying mechanisms may lead to new strategies for improving therapeutic efficacy. Although a number of signaling pathways have been shown to be associated with tumor cell-mediated resistance to immunotherapy, T cell-intrinsic resistant mechanisms remain elusive. Here, we demonstrated that diacylglycerol kinase alpha (Dgka) mediated T-cell dysfunction during anti-PD-1 therapy by exacerbating the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade. Dgka inhibition also enhanced the efficacy of anti-PD-1 therapy. We further found that the expression of DGKA in cancer cells promoted tumor growth via the AKT signaling pathway, suggesting that DGKA might be a target in tumor cells as well. Together, these findings unveiled a molecular pathway mediating resistance to PD-1 blockade and provide a potential therapeutic strategy with combination immunotherapy., (©2021 American Association for Cancer Research.)

K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-ras G12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

System x c - cystine/glutamate antiporter, composed of a light-chain subunit (xCT, SLC7A11) and a heavy-chain subunit (CD98hc, SLC3A2), is mainly responsible for the cellular uptake of cystine in exchange for intracellular glutamate. In recent years, the xCT molecule has been found to play an important role in tumor growth, progression, metastasis, and multidrug resistance in various types of cancer. Interestingly, xCT also exhibits an essential function in regulating tumor-associated ferroptosis. Despite significant progress in targeting the system x c - transporter in cancer treatment, the underlying mechanisms still remain elusive. It is also unclear why solid tumors are more sensitive to xCT inhibitors such as sulfasalazine, as compared to hematological malignancies. This review mainly focuses on the role of xCT cystine/glutamate transporter in regard to tumor growth, chemoresistance, tumor-selective ferroptosis, and the mechanisms regulating xCT gene expression. The potential therapeutic implications of targeting the system x c - and its combination with chemotherapeutic agents or immunotherapy to suppress tumor growth and overcome drug resistance are also discussed., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Ferroptosis is a newly discovered form of iron-dependent oxidative cell death characterized by lethal accumulation of lipid-based reactive oxygen species (ROS). It is distinct from other forms of cell death including apoptosis, necrosis, and autophagy in terms of morphology, biochemistry and genetics., Discussion: Ferroptosis can be induced by system xc- inhibitors or glutathione peroxidase 4 (GPx4) inhibitors, as well as drugs such as sorafenib, sulfasalazine (SAS), and artesunate (ART). Ferroptosis has been recently shown to be critical in regulating growth of tumors, such as hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic carcinoma, and diffuse large B cell lymphoma (DLBCL). Ferroptosis is also associated with resistance to chemotherapeutic drugs and the anti-tumor efficacy of immunotherapy., Conclusion: This review summarizes the mechanism of ferroptosis and its relationship with different types of tumors, to advance our understanding of cell death and to find a novel approach for clinical cancer management., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Immunotherapy has become an important approach for treating different tumours which has shown significant efficacy in numerous clinical trials, especially those using new checkpoint inhibitors and adoptive cell therapy, which have rapidly become widespread after being approved. However, analysis of peripheral immune biomarkers before and after immunotherapy and their relationship to clinical responses and disease prognosis have rarely been performed in clinical trials. In this review, we examine dynamic changes in the immune system before and after therapy by analyzing recent clinical trials of immunotherapy in patients with cancer that focused on checkpoint inhibitors and adoptive cell therapy. Our aim was to identify circulating biomarkers which can specifically predict clinical response and prognosis, as well as toxicities of immunotherapy. Through this approach, we hope to advance our understanding of the mechanisms of immunotherapy with the goal of developing individualized treatment for cancer patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The efficacy of cancer drugs is often compromised due to the existence of biological barriers such as nonspecific distribution, hemorheological flow limitation and endothelial extravasation, impaired delivery across tumor cell membranes and tissue, and multidrug resistance. To overcome these obstacles, Xu et al developed an injectable nanoparticle generator platform to negotiate with the biological barriers and enable self-assembly of nano-balls in situ in order to maximize drug accumulation inside the tumor tissues and hence the therapeutic efficacy. This perspective aims to elaborate the designing strategy, and discuss the mechanism of action of the new drug and the potential for future development of nanoparticulate drugs.

Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM)-based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I) response in dendritic cells (DCs). PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)