Emerging strategies of cell and gene therapy targeting tumor immune microenvironment

Abstract Immunotherapy has profoundly transformed the landscape of cancer treatment, and offered therapeutic opportunities to reverse the immunosuppressive microenvironment. However, the intra-tumoral heterogeneity (ITH) and the evolution towards immune evasion present significant challenges that demand innovative solutions beyond immune checkpoint inhibitors (ICIs). In this context, cell and gene therapy (CGT) emerges as a promising frontier in the new-immunotherapy era with their remarkable flexibility, diversity, and compatibility. In this review, we began with a foundational overview of the classification of CGT in treating solid tumors, and explored how it targets the crosstalk between cancer cells and the tumor immune microenvironment (TIME) from cellular and molecular perspectives. CGT not only remodels the local TIME but also has long-term effects on systemic immune response. Furthermore, this review summarized current challenges and strategic approaches, drawing on insights gained from clinical practice. By bridging mechanistic research with clinical insights, this review underscored the positive feedback from research bench to clinical scenarios. More importantly, we propose that the development of CGT marks the evolution of cancer treatment paradigm: from targeting tumor tissues alone to restoring the disrupted cancer-immune balance as a whole.