Programmable bacteria synergize with PD-1 blockade to overcome cancer cell-intrinsic immune resistance mechanisms. Science immunology Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ-producing bacteria was sufficient to drive systemic tumor antigen-specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3CD4 and CD8 T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ-producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease. 10.1126/sciimmunol.adn9879

Polymeric immunogel prevents tumor recurrence and metastasis by dual activation of innate and adaptive immunity. Bioactive materials Tumor recurrence and metastasis after surgery are important factors affecting patient survival. The immunosuppressed tumor microenvironment after surgery reduces the ability of the immune system to clear residual tumor cells, thus increasing the risk of recurrence and metastasis. Currently, immunotherapy-based adjuvant therapy can effectively inhibit tumor recurrence and metastasis after surgery, but simultaneous and efficient synergistic activation of adaptive and innate immunity is a challenge. Here, we utilized polymeric hydrogel loaded with decitabine (DAC), cisplatin (CDDP) and manganese ions (Mn) as a postoperative filler immunogel to synergistically activate both anti-tumor innate and adaptive immunity. The sustained release of CDDP and DAC burst gasdermin E (GSDME)-mediated pyroptosis and activated adaptive immunity, while Mn enhanced intrinsic immune activation through STING pathway. Such immunogel achieved an encouraging anti-tumor effect with an 80 % total survival rate for recurrent tumors and a 60 % survival rate for metastatic tumors. Considering that this immunogel possesses simple formulation and displays superior anti-tumor effect, this research provided a promising strategy for postoperative cancer therapy. 10.1016/j.bioactmat.2024.11.008