In situ Engineering of Tumor‐Associated Macrophages via a Nanodrug‐Delivering‐Drug (β‐Elemene@Stanene) Strategy for Enhanced Cancer Chemo‐Immunotherapy

Abstract Tumor‐associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant challenge in translational immuno‐oncology. Here, we report an innovative nanodrug‐delivering‐drug (STNSP@ELE) strategy that leverages two‐dimensional (2D) stanene‐based nanosheets (STNSP) and β‐Elemene (ELE), a small‐molecule anticancer drug, to overcome TAM‐mediated immunosuppression and improve chemo‐immunotherapy. Our results demonstrate that both STNSP and ELE are capable of polarizing the tumor‐supportive M2‐like TAMs into a tumor‐suppressive M1‐like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intratumoral ratio of M1/M2‐like TAMs, enhancing the population of CD4 + and CD8 + T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo‐immunotherapeutic nanoplatform has immune‐modulatory capabilities that can overcome TAM‐mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug‐delivering‐drug strategy in developing other nano‐immunotherapeutics and treating various types of immunosuppressive tumors.