Multifunctional exosome-driven tumor immunotherapy sensitization: converting intratumoral bacteria into antitumor fighters.

Abstract

Utilizing intratumoral bacteria to reprogram tumor-associated macrophages (TAMs) into a tumoricidal M1 phenotype holds great potential in cancer immunotherapy. However, intratumoral bacteria cunningly hide inside tumor cells to evade the surveillance of TAMs. Herein, we utilize dead tumor cells as bridges to connect TAMs with intratumoral bacteria. We constructed a multifunctional exosome loaded with ferroptosis inducer Fe₃O₄ nanoparticles and photothermal agent ICG to convert intratumoral bacteria into antitumor fighters to achieve tumor immunotherapy sensitization: 1) The multifunctional exosomes enable a synergistic enhancement of ferroptosis and photothermal therapy, efficiently inducing the death of tumor cells and intratumoral bacteria. 2) The killed tumor cells not only exhibit enhanced immunogenicity, but also promote the phagocytosis of hidden bacteria by macrophages when combined with CD47 blockade. 3) The engulfed bacteria could serve as antitumor fighters to polarize TAMs into tumoricidal M1 phenotype. The immunotherapy sensitization driven by the multifunctional exosomes provokes a robust antitumor immunity, promotes the intratumoral infiltration of T cells, and ultimately results in effective suppression of both tumor growth and metastasis.