Nanomedicine-based sensitization and resistance reversal in immunotherapy of clear cell renal cell carcinoma: from tumor microenvironment to precision delivery

Clear cell renal cell carcinoma poses unique challenges for immunotherapy, particularly with immune checkpoint inhibitors. Many ccRCC tumors exhibit an "immune-cold" tumor immunosuppressive microenvironment (TIME), characterized by poor T cell infiltration and multiple immunosuppressive barriers, leading to primary or acquired resistance to ICIs. Approaches to convert these tumors into "immune-hot" (T cell-inflamed) states are critical for improving therapeutic outcomes. Nanomedicine offers promising solutions by modulating the broader tumor microenvironment (TME) and enabling precision delivery of immune-modulatory agents. In this review, we highlight how nanotechnology-based platforms can alleviate hypoxia and acidity in the TME, reprogram suppressive myeloid cells within the TIME (e.g., myeloid-derived suppressor cells and tumor-associated macrophages), and synergize with ICIs and targeted therapies. We summarize recent advances in ccRCC and ccRCC-relevant preclinical models, distinguishing direct RCC evidence from hypothesis-generating findings derived from other solid tumors. These integrative nano-immunotherapy approaches aim to overcome immunoresistance in ccRCC, turning immunologically "cold" tumors "hot" and improving the depth and durability of anti-tumor immune responses.