Jul 2026· Signal Transduction and Targeted Therapy· Vol 11· 0 citations· 283 references
Medicine
TL;DR
Recent advances in nanomedicine-enabled delivery systems, microenvironmental modulation, and combinatorial strategies are overcoming challenges and position in situ cancer vaccination as a patient-tailored, broadly applicable immunotherapy capable of eliciting durable and systemic antitumor immunity.
Abstract
In situ cancer vaccination, also termed intratumoral immunotherapy, transforms the tumor microenvironment into an endogenous vaccine platform by leveraging the tumor itself as a source of antigens. Unlike conventional tumor-associated antigen (TAA) or personalized neoantigen vaccines that require predefined targets and complex manufacturing, in situ cancer vaccination presents the tumor’s full antigenic repertoire, including TAAs, neoantigens, post-translationally modified epitopes, cryptic peptides, and viral antigens within their native context. This broad antigen exposure elicits robust polyclonal cytotoxic T-cell responses, facilitates epitope spreading, and reduces immune escape driven by tumor heterogeneity. The therapeutic efficacy of this approach arises from the coordinated activation of multiple immune mechanisms. Programmed cell death pathways, including immunogenic apoptosis, pyroptosis, necroptosis, and ferroptosis, release tumor antigens and danger-associated molecular patterns (DAMPs) that promote dendritic-cell activation, efficient cross-presentation, and the priming of durable effector and memory T cells. The incorporation of potent adjuvants and advanced delivery platforms enhances innate-adaptive crosstalk and helps remodel the immunosuppressive tumor microenvironment. Despite these advantages, clinical translation is limited by inconsistent induction of immunogenic cell death, suboptimal intratumoral retention of therapeutics, and barriers to T-cell infiltration. Recent advances in nanomedicine-enabled delivery systems, microenvironmental modulation, and combinatorial strategies, particularly with immune checkpoint blockade, are overcoming these challenges. Collectively, these innovations position in situ cancer vaccination as a patient-tailored, broadly applicable immunotherapy capable of eliciting durable and systemic antitumor immunity.
Irradiation-based cancer vaccines represent a promising immunotherapeutic strategy, primarily comprising in vitro-irradiation-prepared cancer vaccine (ICV) and in situ-irradiation-induced cancer vaccine (ISCV). ICV leverages the complete antigenic repertoire of irradiation-inactivated tumor cells to activate polyclonal T-cell responses via antigen-presenting cells (APCs), thereby overcoming tumor heterogeneity. In contrast, ISCV directly transforms the tumor into an endogenous "antigen factory" through focal irradiation-induced immunogenic cell death, which releases tumor antigens and danger signals to initiate systemic anti-tumor immunity and the abscopal effect. Despite their potential, challenges such as optimal dosing, the immunosuppressive tumor microenvironment, and personalized regimen design remain. Future clinical translation is poised to leverage combination strategies with immune checkpoint inhibitors, cytokines, or nanotechnology-based delivery systems to enhance therapeutic efficacy. Here, we review the action and effects of irradiation, the mechanisms underlying antigen presentation and immune activation of the two vaccines, summarize the progress of relevant clinical trials, and provide an outlook on future development directions-with the aim of offering references for the development and clinical translation of new vaccines. Despite their fundamental divergence in antigen sourcing (exogenous and endogenous origins), both modalities act through APC-mediated adaptive immune responses. Distinct translational obstacles exist for each platform, which requires biomarker-guided patient selection and ethically justified combination therapies to realize safe and equitable clinical translation.
Jiangwen Tian, Xianglong Feng, Boyi Yu et al.· Critical reviews in oncology...· 0 citations
Therapeutic cancer vaccines are designed to initiate tumor-specific immunity, yet their clinical success depends not only on antigen selection but also on the capacity to overcome the profoundly suppressive tumor microenvironment. Within tumors, abnormal vasculature, hypoxia, nutrient competition, acidic pH, and suppressive myeloid and stromal cells collectively constrain antigen presentation, T-cell priming, trafficking, and effector function, often converting otherwise immunogenic vaccination into an ineffective immune stimulus. Recent advances in neoantigen discovery, dendritic cell engineering, and nucleic acid-based vaccine platforms have improved the precision of antigen delivery, but these gains remain insufficient unless vaccine-induced responses can be sustained and executed within the hostile metabolic and immunologic landscape of the tumor niche. In this context, the tumor microenvironment is not merely a barrier to be overcome, but an active determinant of vaccine outcome that shapes immune editing, promotes exhaustion, and limits intratumoral expansion of cytotoxic lymphocytes. Accordingly, the most promising therapeutic strategies now combine vaccination with checkpoint blockade, radiotherapy, stromal remodeling, or metabolic reprogramming to recondition the tumor ecosystem and permit productive antitumor immunity. Here, we discuss how tumor microenvironmental constraints govern vaccine performance, review emerging platform technologies, and outline combinatorial strategies aimed at converting immune priming into durable tumor control.
Zhangzhou Shen, Qin-Qin Feng, Fen Wang et al.· Vaccines· 0 citations
ABSTRACT Cancer immunotherapy has reshaped modern oncology by enabling the immune system to recognize and eliminate malignant cells. However, many solid tumors still respond poorly because of weak T‐cell activation and an immunosuppressive tumor microenvironment. Bacterial superantigens (SAgs) represent a unique class of immunomodulatory proteins capable of overcoming these limitations through direct activation of large T‐cell populations. Unlike conventional antigens, superantigens bypass classical antigen processing by simultaneously binding major histocompatibility complex class II molecules and T‐cell receptor Vβ domains, triggering rapid cytokine release and extensive immune activation. Although this potent mechanism has historically been associated with severe systemic toxicity, recent advances in protein engineering and targeted delivery have renewed interest in their therapeutic potential. This review discusses the structural and immunological basis of superantigen activity and highlights emerging strategies designed to improve tumor specificity and safety, including engineered low‐toxicity variants, antibody‐superantigen fusion proteins, nanoparticle‐based delivery systems, and tumor‐targeted constructs. We further examine how superantigens reshape the tumor microenvironment and synergize with immune checkpoint blockade, adoptive cell therapies, and other T‐cell‐redirecting approaches. Together, these advances position engineered superantigens as promising immune‐amplifying platforms with the potential to complement existing cancer immunotherapies and improve responses in poorly immunogenic tumors.
U. Y. Virk, H. A. Malik, M. Anwer et al.· The FASEB Journal· 0 citations
Despite the success in infectious diseases, mRNA vaccines have inherent limitations in stability and immunogenicity. Non-small cell lung cancer remains the leading cause of cancer-related death worldwide, with poor prognosis in advanced stages, underscoring the urgent need for novel therapeutic strategies. Previously, we have developed a scarless circular RNA synthesis platform NeoAna that exhibited enhanced stability and long-lasting antigen expression with minimal cytotoxicity compared to mRNA. In this study, we construct circRNA vaccine using NY-ESO-1 as the antigen and deliver circRNA vaccine with lipid nanoparticles. The circRNA vaccine elicited robust innate and adaptive immune responses both in vitro and in vivo. It demonstrated superior antitumor efficacy relative to mRNA vaccine, achieving 93.1% tumor inhibition when combined with immune checkpoint blockade. Prophylactic vaccination prevented tumor establishment, while adjuvant therapy conferred protection against tumor re-challenge, highlighting durable immune memory. Mechanistically, circRNA vaccine promoted dendritic cell maturation and enhanced tumor infiltration of T cells, and mediated antitumor immunity in a CD8+ T cell-dependent manner. Additionally, single-nucleus RNA sequencing revealed that it remodeled the tumor microenvironment toward a pro-inflammatory and antitumor phenotype. Following circRNA vaccination, the proportions of cytotoxic T cells, pro-inflammatory macrophages, and antigen-presenting cancer-associated fibroblasts were all increased within the tumor microenvironment, accompanied by activation of immunity-related signaling pathways. In conclusion, our findings demonstrate the immunogenicity and therapeutic potential of the NeoAna circRNA-based therapeutic vaccine, supporting its further evaluation in clinical trials.
Shaoyi Chen, Lin Weng, Xu Liu et al.· Cancer Letters· 0 citations
Cancer immunotherapy has emerged as a transformative therapeutic strategy that harnesses the host immune system to recognize and eliminate malignant cells. This review provides a comprehensive overview of current immunotherapeutic approaches, including immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), cancer vaccines, dendritic cell (DC)-based vaccines, chimeric antigen receptor (CAR)-T cell therapy, and oncolytic virus therapy. The mechanisms of action, therapeutic applications, and clinical benefits of each modality are discussed. Monoclonal antibodies selectively target tumor-associated antigens, whereas ICIs restore antitumor immunity by blocking inhibitory immune checkpoints. Cancer vaccines and DC-based vaccines enhance antigen-specific immune responses, while CAR-T cell therapy employs genetically engineered T cells to achieve highly specific tumor targeting. Oncolytic viruses selectively infect and destroy tumor cells while stimulating systemic antitumor immune responses. The review also addresses major challenges associated with immunotherapy, including immune-related adverse events, variable patient responses, and the development of therapeutic resistance. Particular emphasis is placed on the tumor microenvironment (TME), whose complex cellular and molecular interactions critically influence tumor progression, immune evasion, and treatment efficacy. Furthermore, the potential of combination immunotherapeutic strategies to improve clinical outcomes and achieve durable responses is highlighted. Finally, emerging applications of immunotherapy beyond oncology are briefly discussed. Collectively, this review summarizes recent advances in cancer immunotherapy and provides insights into current challenges and future directions for the development of more effective and personalized therapeutic strategies. Unlike previous studies focusing solely on specific therapeutic modalities, this review uniquely integrates fundamental cellular mechanisms, clinical milestones, TME dynamics, and current combination strategies, while also highlighting emerging non-oncology applications of Immunotherapeutics.
Unknown authors· Al-Mustaqbal Journal of Phar...· 0 citations
Overall, cancer vaccines are unlikely to become universal stand-alone treatments for advanced solid tumors, and their most credible role may emerge in molecularly selected patients, adjuvant therapy, minimal residual disease, virus-associated malignancies, and rational combinations with checkpoint inhibitors or tumor microenvironment-modulating agents.
Dario Rusciano· Frontiers in Cell and Develo...· 0 citations
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