Challenges and perspectives of CAR-T cell therapy in solid tumours: insights from gastric cancer

Gastric cancer (GC) remains a significant challenge as it is one of the most prevalent and lethal malignancies worldwide. Due to its complexity characterised by diverse histological subtypes and genetic mutations, its management and treatment remain a substantial challenge. Recent advancements in surgery, chemotherapy, and radiation therapy have only marginally improved the prognosis for advanced GC, underscoring the urgent need for innovative therapeutic strategies. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a breakthrough in haematologic malignancies and is now being investigated as a potential treatment for solid tumours. The remarkable efficacy of CAR-T in GC has been demonstrated in both preclinical and clinical studies. Potential biomarkers for GC treatment include CLDN18.2, MSLN, CEA, EpCAM, MUC1, HER2, FOLR1, and NKG2DL. However, applying CAR-T cells directed against GC still faces considerable challenges. Novel CAR designs have the potential to enhance CAR-T cell therapy for GC by facilitating T cell infiltration, enhancing T cell persistence, reducing on-target off-tumour toxicity, improving tolerance to the immunosuppressive tumour microenvironment (TME), and bolstering interactions with heterogeneous antigens. This review summarises relevant preclinical studies and clinical progress in CAR-T cell therapy for GC, evaluates its therapeutic potential and safety, discusses current challenges, and outlines future directions for clinical translation.