Tissue-localized immunoengineering for in situ reprogramming of immune cells in cancer therapy

Traditional ex vivo engineered immune cell therapies, such as CAR-T and TCR-engineered T cells, have revolutionized cancer treatment but face hurdles in solid tumors. These centralized, systemically deployed approaches are biologically detached from tumor ecosystems, resulting in high manufacturing costs, systemic toxicity, and poor persistence. To overcome these limitations, an emerging paradigm shifts focus toward Tissue-Localized Immunoengineering. This strategy programs, activates, regulates, and renews immune cells directly within their native tissue microenvironments. By operating in vivo, it transforms engineered immunity from a lab-derived cellular product into a spatially precise, evolution-aware, and environment-aware biological system. This approach preserves tissue-resident identity, epigenetic fidelity, and ecological balance, offering enhanced timeliness, quantitative control, and long-term oncological resilience. This review summarizes the biological justification, mechanisms, delivery success vectors, design principles, and translational barriers that are relevant to in vivo tissue-localised immunoengineering for cancer, both from a biological and molecular standpoint. Specific focus on tumor-responsive sensing systems, synthetic genetic circuits, delivery efficiency in solid tumors, programmable safety mechanisms, and new ideas for clinical translation.