Mitochondria-targeted photothermal-chemodynamic therapy enhances checkpoint blockade immunotherapy on colon cancer

Immunotherapy has emerged as a hotspot for cancer treatment. However, the response rate of monotherapy remains relatively low in clinical settings. Photothermal therapy (PTT), which employs light energy to ablate tumors, can also activate tumor-specific immune responses. This effect has been attributed in several studies to the release of damage-associated molecular patterns (DAMPs) triggered by mitochondrial injury. We propose that mitochondria-targeted PTT may better synergize with immunotherapy. Herein, we constructed a multifunctional nanoplatform that enables mitochondria-targeted photothermal-chemodynamic combination therapy by conjugating indocyanine green-thiol (ICG-SH) and mercaptoethyl-triphenylphosphonium (TPP-SH) onto polyvinyl pyrrolidone (PVP)-coated gold-copper nanoparticles (AIT). Upon near-infrared light (NIR) irradiation, AIT ablates cancer cells and amplifies the effect of chemodynamic therapy (CDT), thereby inducing apoptosis in the tumor. The combination of CDT and PTT promotes immunogenic cell death, which could synergize with checkpoint blockade immunotherapy. In a bilateral mouse colon cancer model, we observed complete eradication of light-irradiated primary tumors and significant inhibition of distant untreated tumors in the group treated with AIT plus anti-PD-1 (αPD-1). We found a significant increase in serum levels of pro-inflammatory factors, including interleukin-6 (IL-6), interferon-<i>γ</i> (IFN-<i>γ</i>), and tumor necrosis factor-<i>α</i> (TNF-<i>α</i>), following PTT/CDT/immunotherapy treatment, suggesting effective activation of the immune response. The enhanced immunogenicity caused by AIT with αPD-1 treatment resulted in efficient antigen presentation, as indicated by the increased infiltration of dendritic cells (DCs) into the tumor-draining lymph nodes (LNs). We also observed enhanced infiltration of CD8⁺ T cells in distant tumors in the AIT with αPD-1 group compared to αPD-1 alone. Hence, mitochondria-targeting represents an effective strategy to potentiate the combination of photothermal, chemodynamic, and immune checkpoint blockade therapies for the treatment of metastatic cancer.