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

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 beta-Elemene (ELE), a smallmolecule 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 nanoimmunotherapeutics and treating various types of immunosuppressive tumors.

Automated summary

This study reports an innovative nanodrug-delivering-drug strategy utilizing two-dimensional stanene-based nanosheets (STNSP) and beta-Elemene (ELE) to overcome TAM-mediated immunosuppression in solid tumors. The results demonstrate that STNSP and ELE can polarize tumor-supportive M2-like TAMs into tumor-suppressive M1-like phenotype and enhance the antitumor response. This research not only shows the immune-modulatory capabilities of the STNSP@ELE chemo-immunotherapeutic nanoplatform in overcoming TAM-mediated immunosuppression but also highlights its potential in developing other nanoimmunotherapeutics for treating immunosuppressive tumors.