TL;DR
Developing a mechanistic framework that combines intrinsic T cell reprogramming with adaptation to the tumor context will be crucial for extending durable T cell-mediated immunity to solid cancers.
The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.
Tumor microenvironment-resident immunosuppressive cells-comprising myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages-constitute primary obstacles to effective cancer immunotherapy. Advances in single-cell and spatial multi-omics have uncovered their substantial functional heterogeneity, tissue-adaptive reprogramming, and organ-specific architectures distinguishing primary tumors from metastatic lesions. Beyond canonical immune checkpoint pathways, non-canonical regulatory layers--including metabolic-immune crosstalk, epigenetic regulation, microbiome-mediated distant signaling, and therapy-induced adaptive remodeling-further reinforce treatment resistance. Based on these mechanistic insights, systematic synergistic strategies have been developed, such as multi-pathway checkpoint blockade, ADC-immunotherapy combinations, temporally and spatially optimized conventional therapies, and targeted agents that deplete or reprogram suppressive populations. Emerging biomarkers, repurposed pharmaceuticals, and pan-cancer therapeutic principles are refining patient stratification and combination regimens. This review offers a comprehensive framework for understanding and surmounting immunosuppressive barriers in cancer therapy.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies. Not applicable.
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical success in hematological malignancies. However, its efficacy in solid tumors such as lung cancer remains constrained by the immunosuppressive tumor microenvironment (TME). Aberrant vascular architecture and dense stroma constitute major physical barriers that hinder CAR T cell infiltration. Additionally, an immunosuppressive cellular network, dominated by myeloid-derived suppressor cells and tumor-associated macrophages, further restricts CAR T cell expansion and function. Moreover, immune checkpoint signaling, inhibitory cytokines, dysregulated chemokine gradients, and metabolic reprogramming under hypoxia collectively create a hostile biochemical and metabolic milieu that drives CAR T cell dysfunction and exhaustion. This review systematically outlines these multifactorial barriers within the lung cancer TME and discusses emerging strategies, including combinatorial approaches, engineered CAR T designs, and microenvironment-modulating platforms, that aim to improve the therapeutic efficacy of CAR T cell therapy in lung cancer.
Next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.
Small cell lung cancer (SCLC) is an aggressive and immunologically "cold" malignancy characterized by profound immunosuppression and limited responsiveness to immunotherapy. Its tumor immune microenvironment (TIME) exhibits defective antigen presentation, suppressive cytokine signaling, and abnormal stromal-metabolic interactions that collectively restrict immune activation and promote tumor progression. Overcoming this immune-cold state is an urgent prerequisite for improving therapeutic efficacy and achieving durable responses in SCLC.Converting SCLC from an immune-cold to an immune-active state requires integrated therapeutic strategies that relieve immunosuppression, restore antigen presentation, enhance effector lymphocyte infiltration and function, and overcome metabolic and stromal barriers that shape the suppressive TIME. This review integrates mechanistic insights with emerging therapeutic strategies for remodeling the SCLC TIME, focusing on radiotherapy, immunomodulatory therapies, stromal-targeted therapies, epigenetic therapy, and engineered immunotherapy platforms such as delta-like ligand 3 (DLL3)-directed bispecific T-cell engagers, CAR-T and cytokine-armored cells, biological vector-based immunotherapies, and nano-immunotherapy platforms. These advances outline a translational framework for converting immune-cold SCLC into an immune-responsive disease and achieving durable immunotherapeutic efficacy.
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