Chlorin e6 and Regorafenib Assemblies to Boost Photodynamic Immunotherapy through PD-L1 Downregulation and Tumor-Associated Macrophage Reprogramming.

The effectiveness of immunotherapy is significantly limited by the inherently low immunogenicity and immunosuppressive phenotypes of tumors. To address this challenge, we develop assemblies composed of chlorin e6 and regorafenib (designated as CeRe), which combine photodynamic therapy (PDT) with immune regulatiing functions. CeRe exhibits uniform nanoscale distribution and good stability without requiring additional carriers. Upon light activation, CeRe eradicate tumor cells via PDT-induced reactive oxygen species (ROS) while simultaneously triggering immunogenic cell death (ICD). Furthermore, CeRe downregulates PD-L1 expression in tumor cells, promotes macrophage polarization, and relieves the immunosuppressive tumor microenvironment (TME). These synergistic immunomodulatory effects substantially improve tumor responsiveness to αPD-L1 treatment, leading to the effective inhibition of both primary and metastatic tumor growth. Collectively, this work presents a carrier-free nanodrug assembly strategy with multifaceted mechanisms, offering a promising approach for precise tumor therapy and metastasis suppression.