Hydrophilic porphyrin copolymers combined with autophagy inhibitors enhance tumor photothermal/photodynamic therapy.

Synergistic photodynamic and photothermal therapy (PDT/PTT) holds immense promise for cancer treatment, yet its efficacy is often compromised by limited photosensitizer performance, glutathione (GSH)-mediated ROS quenching, and tumor-protective autophagy. Herein, we developed a GSH-responsive hydrophilic porphyrin copolymer (PPS) that covalently integrates porphyrin into the polymer backbone, ensuring high loading capacity and minimal carrier-related toxicity. PPS exhibits robust absorption around 800 nm, enabling simultaneous PDT and PTT under a single NIR laser. By incorporating the autophagy inhibitor chloroquine (CQ), the resulting CQ@DPPS nanosystem achieves multi-modal synergy: intracellularly, CQ not only inhibits phototherapy-induced autophagic flux to suppress cell survival but also facilitates the lysosomal escape of photosensitizers, heightening programmed cell death via Bcl-2 inhibition and Caspase-3 activation. Crucially, CQ@DPPS significantly activates NK cell-mediated innate immune surveillance and enhances the secretion of granzyme B (GZMB) in NK cells by downregulating MHC-I expression on the surface of tumor cells. In vivo, CQ@DPPS combined with 808 nm irradiation achieved complete tumor regression in HCT116-bearing mice and significantly attenuated hepatic metastasis. This work provides a potent strategy to overcome phototherapy resistance through the integration of autophagy inhibition, dual-mode phototherapy, and innate immune activation. STATEMENT OF SIGNIFICANCE: Clinical translation of PDT/PTT therapy is hindered by inefficient photosensitizer delivery, GSH-mediated ROS depletion, and cytoprotective autophagy in tumors. Here, we report a GSH-responsive hydrophilic porphyrin copolymer with porphyrin covalently integrated into the polymer backbone, enabling high loading, reduced carrier burden, and effective 808 nm-triggered PDT/PTT. Co-delivery of CQ in the CQ@DPPS nanosystem not only suppresses protective autophagic flux, but also promotes lysosomal escape, mitochondrial apoptosis, and NK cell-mediated antitumor immunity through reduced MHC-I expression and increased GZMB secretion. This multi-mechanistic platform achieved complete tumor regression and reduced hepatic metastasis in vivo, offering a promising biomaterial strategy to overcome major barriers in phototherapy and facilitate clinical translation.