Emerging Strategies of Cell and Gene Therapy Targeting Tumor Immune Microenvironment

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