Smart nanodelivery systems targeting tumor-associated macrophage reprogramming to potentiate cancer immunotherapy: pharmacological mechanisms, delivery strategies and translational perspectives

Cancer immunotherapy, particularly immune checkpoint blockade, has substantially changed the treatment landscape for multiple malignancies, but clinical benefit remains limited by low response rates, primary tolerance, and acquired resistance. Tumor-associated macrophages (TAMs) are abundant and highly plastic myeloid cells in the tumor immune microenvironment. They contribute to tumor progression and immunotherapy resistance by suppressing T-cell recruitment and effector function, promoting angiogenesis, remodeling extracellular matrix, regulating metabolism, and expressing immune-checkpoint-related molecules. TAMs exhibit overlapping functional states beyond a fixed M1/M2 dichotomy, shaped by cytokines, chemokines, pattern-recognition receptors, kinase-transcription factor networks, hypoxia, lactate, and redox signals. Reprogramming immunosuppressive TAMs toward inflammatory, antigen-presenting, and T-cell-supporting phenotypes has therefore become an important pharmacological strategy to enhance antitumor immunotherapy. Smart nanodelivery systems can improve the in vivo stability, tumor accumulation, TAM exposure, and spatiotemporal release of immunomodulators, small-molecule inhibitors, nucleic acid therapeutics, cytokines, and macrophage immune-checkpoint modulators, thereby improving efficacy while reducing systemic toxicity. This review summarizes the rationale for targeting TAMs in cancer immunotherapy, the mechanisms regulating TAM functional states, the design principles of smart nanodelivery systems, nanomedicine-mediated reprogramming strategies, pharmacodynamic outcomes, pharmacokinetic and safety issues, preclinical evaluation methods, translational barriers, and future directions.