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The clinical efficacy of cancer immunotherapy remains limited in many solid tumors due to the presence of immunosuppressive microenvironments, dense extracellular matrix (ECM) barriers, and aberrant vasculature, all of which impede drug penetration and immune cell infiltration. This talk highlights our recent advances in engineering nanocarriers to reprogram the tumor microenvironment and enhance anti-tumor immune responses. We demonstrate how the targeted delivery of small molecules, therapeutic gases, genes, cytokines, and enzymes via nanoscale platforms can normalize tumor vasculature, increase T cell infiltration, and synergize with cancer vaccines and immune checkpoint blockade across various malignancies. Furthermore, we present an in situ gel-based cancer vaccine incorporating chemo-immunotherapeutic agents, STING agonists, or engineered dendritic cells to promote immunogenic cell death and durable post-surgical anti-tumor immunity. By utilizing rational nanocarrier design, we achieve precise modulation of both stromal and immune compartments—showing the potential of nanotechnology to convert “cold” tumors into immunologically active ones and offering a blueprint for clinically translatable strategies in combination immunotherapy.