Photothermal-gas combination therapy promotes checkpoint blockade immunotherapy in colon cancer

Checkpoint blockade immunotherapy emerges as a potential cure of cancer, but the monotherapy suffers from a low response rate in clinic. Photothermal therapy (PTT) that harvests light energy to ablate tumor is reported to activate tumor-specific immune response, meanwhile nitric oxide (NO) is considered to involve in immune regulation. Herein, we designed a multifunctional nanoplatform that enables photothermal-gas combination therapy by conjugating indocyanine green-thiol (ICG-SH) and s-nitrosoglutathione (GSNO) onto polyvinyl pyrrolidone (PVP)-coated gold nanoparticles (AIG). Upon near-infrared light (NIR) irradiation, AIG heats up the cancer cells and triggers NO release from GSNO, thus inducing apoptosis in the tumor. We found the combination of NO with photothermal treatment causes immunogenic cell death, which should synergize with checkpoint blockade immunotherapy. In the mouse colon cancer bilateral model, we observed complete eradication of light-irradiated tumors and suppression of distant untreated tumors in the AIG with anti-PD-1 (αPD-1) group. We detected significant increase of pro-inflammatory factors in serum, such as interferon- (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) after PTT-gas-immunotherapy treatment, indicating the successful activation of the immune response. The improved immunogenicity caused by AIG with αPD-1 group allows for efficient antigen presentation, as evidenced by the increased infiltration of dendritic cells (DCs) into the tumor-draining lymph nodes (LNs). We also found promoted infiltration of CD8⁺ T cells in the untreated tumors in the AIG with αPD-1 group comparing to αPD-1 alone. Therefore, phototermal-gas-immune checkpoint blockade combination therapy represents a new promising treatment of metastatic cancer.