Abstract Background Chimeric Antigen Receptor T‐cell (CAR‐T) therapy has evolved from its initial application in hematological cancers to treating solid tumors and autoimmune diseases. Despite iterative advancements in CAR design improving efficacy and safety, challenges including limited persistence, immune‐related toxicities, tumor resistance mechanisms, and barriers posed by the tumor microenvironment (TME) remain critical obstacles. Methods This review synthesizes current evidence on CAR‐T resistance mechanisms and therapeutic strategies. Key approaches analyzed include CAR design optimization (e.g., dual‐targeting), pre‐infusion tumor burden reduction, combination therapies to mitigate immune suppression, and cytokine support (e.g., IL‐2/IL‐15) to enhance persistence. The role of the TME (hypoxia, metabolic competition, immunosuppressive factors) and tumor‐intrinsic resistance drivers (antigen loss, anti‐apoptotic signaling) are systematically evaluated. Results Major resistance mechanisms include antigen escape (masking/loss), high tumor burden, and TME‐mediated suppression (hypoxia, immune checkpoints). Clinical challenges involve manufacturing delays, insufficient CAR‐T cytotoxicity, and poor persistence. Strategies such as dual‐target CARs, preconditioning regimens, and cytokine‐augmented persistence demonstrate preclinical/clinical promise in overcoming these limitations. Conclusions CAR‐T therapy holds transformative potential but requires addressing resistance and toxicity barriers. Future directions include allogeneic CAR‐T platforms, in vivo CAR‐T delivery, and novel combinatorial approaches. While these innovations offer exciting prospects, scalability, safety, and long‐term efficacy necessitate further translational and clinical research.
Yao et al. (Sun,) studied this question.