Frontiers and challenges of immune cell therapy research in solid tumors

<p indent="0mm">Tumor immune cell therapy employs activated and modulated patient or donor immune cells to recognize and kill tumor cells, thereby inhibiting tumor growth and spread. Currently, the main forms of immune cell therapy include chimeric antigen receptor T-cell (CAR-T), T-cell receptor-engineered T-cell (TCR-T), tumor-infiltrating lymphocyte (TIL), and natural killer (NK) cell therapies. The success of CAR-T therapy in hematological malignancies has accelerated the development of T-cell-based immune cell therapies for solid tumors. Recently, Lifileucel was granted accelerated approval by the FDA for patients with melanoma, marking the first approved TIL therapy and the first T-cell therapy approved for solid tumors. Moreover, CAR-T therapy targeting CLDN18.2 has exhibited promising efficacy in gastrointestinal tumors, and GD2-targeting CAR-T therapy has obtained encouraging results in gliomas, while TCR-T therapy targeting tumor-associated antigens (including NY-ESO and MAGE-A3) has demonstrated significant antitumor activity in diseases such as synovial sarcoma and uveal melanoma. However, the effective response rate and beneficiary population of immune cell therapy remain limited in most solid tumors, owning to tumor antigen heterogeneity, infiltration obstacles, suppressive immune microenvironments, and limited cell source availability. With advancements in scientific and technological approaches such as synthetic biology, genetic engineering, high-throughput sequencing, and the development of biomaterials, next-generation immune cell technologies are rapidly evolving to enhance efficacy, safety, and cell source expansion. Overexpression of chemokine receptors and cytokines, knockout of immune inhibitory signaling molecules, and combination therapies such as chemotherapy, radiotherapy, and immune checkpoint blockade have made substantial progress in improving the immunosuppressive environment. Research on multi-target tandem, Boolean logic designs, and innate immune cells has shown the potential for enhancing safety. Universal cells, nonviral vectors, and <italic>in vivo</italic> delivery platforms also present possibilities for reducing costs and increasing cell sources in the future. This review systematically summarizes the research progress and main challenges of immune cell therapy in solid tumors and suggests future research directions. Through continuous in-depth basic research, interdisciplinary and innovative integration, and leveraging China’s abundant clinical resources to facilitate bidirectional transformation between basic research and clinical studies, greater progress and development in the field of immune cell therapy for solid tumors are expected.