Natural nanomaterials for cancer immunotherapy: mechanisms, evidence and translational prospects

Cancer immunotherapy, which reactivates the host immune system to recognize and eliminate malignant cells, has become the fourth major therapeutic modality after surgery, radiotherapy and chemotherapy. Its clinical benefit, however, has long been limited by tumor immune evasion, immune-related adverse events and the low efficiency of drug delivery. Natural nanomaterials, including extracellular vesicles, plant-derived exosome-like nanovesicles, cell membrane-coated biomimetic nanoparticles, virus-like particles, protein cage nanostructures, and natural polysaccharide- and protein-based nanoparticles, are derived from endogenous biomolecules or native biological structures. They generally possess excellent biocompatibility, low immunogenicity and limited toxicity, and their surface-displayed natural ligands allow active recognition of tumor tissue and immune cells, which is making them important tools for overcoming the current bottlenecks of immunotherapy. This review systematically summarizes the classification system of natural nanomaterials and the methods used to characterize their physicochemical properties. Drawing on classical colloid chemistry and drug release kinetic models, it describes their mechanisms of action in remodeling the immunosuppressive tumor microenvironment, regulating macrophage polarization, modulating immune checkpoint pathways and delivering immunostimulatory molecules. Representative natural nanoplatforms are then compared using published quantitative data covering particle size and surface potential, in vivo antitumor efficacy and effect sizes reported in clinical meta-analyses. On this basis, the review discusses the key scientific problems that remain to be solved, including batch-to-batch consistency, in vivo metabolism and clearance, long-term toxicological evaluation and regulatory approval, and considers the translational prospects of combining natural nanomaterials with existing immune checkpoint inhibitors, adoptive cell therapy and cancer vaccines. The aim is to provide a systematic reference for in-depth research and clinical translation of natural nanomaterials in cancer immunotherapy. In particular, this review identifies albumin nanoparticles as currently possessing the strongest translational momentum, while recognizing extracellular vesicles as the most transformative long-term platform; systematically addresses the molecular cascade of macrophage M2-to-M1 reprogramming; analyzes barriers to extracellular vesicle scale-up production; explores synergistic combinations with CAR-T cell therapy, cancer vaccines, and immune checkpoint inhibitors; and proposes multi-level strategies to bridge the preclinical-to-clinical translation gap.