TNT-Mediated Mitochondrial Transfer in Cancer Immunotherapeutic Resistance

Despite the transformative advances that have been made in cancer immunotherapy, primary and acquired resistance remain prevalent, limiting durable clinical benefits. Mechanistic studies on immunotherapeutic resistance have largely focused on genetic, transcriptional, signaling, and metabolic programs within tumor and immune cells, with organelle physical routes and metabolic exchange across the tumor-host interface remaining relatively underexplored. Tunneling nanotubes (TNTs), membranous conduits that mediate long-range intercellular exchange, are increasingly implicated in tumor microenvironment remodeling. Thus, TNT-mediated mitochondrial transfer may represent an underexplored intercellular communication axis that can potentially influence tumor adaptation and immunotherapeutic responses. By enabling tumor cells to acquire functional mitochondria from neighboring stromal or immune cells, TNT-associated transfer may reinforce oxidative metabolism, redox homeostasis, and survival under immune and therapeutic pressure. Conversely, although the functional consequences of mitochondrial exchange are strongly dependent on the donor-recipient context, the transfer of tumor-derived mitochondria may result in the reprogramming of recipient immune or stromal cells and favor immunosuppressive states. However, direct evidence establishing TNT-mediated mitochondrial transfer as a causal determinant of immunotherapeutic resistance remains limited and varies significantly across therapeutic modalities. This review discusses the molecular mechanisms governing TNT formation and mitochondrial trafficking, examines the metabolic and immunological consequences of bidirectional tumor-host mitochondrial exchange, critically evaluates evidence linking these processes to distinct immunotherapeutic modalities, and discusses strategies and experimental priorities for their therapeutic translation.