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 tumormicroenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significantchallenge 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. Ourresults demonstrate that both STNSP and ELE are capable of polarizing the tumor-supportive M2-like TAMs into atumor-suppressive M1-like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivomouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantlyincreasing the intratumoral ratio of M1/M2-like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytesand mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, therebypromoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo-immunother-apeutic nanoplatform has immune-modulatory capabilities that can overcome TAM-mediated immunosuppression insolid tumors, but also highlights the promise of this nanodrug-delivering-drug strategy in developing other nano-immunotherapeutics and treating various types of immunosuppressive tumors.