A tumor-microenvironment-adaptive peptide-based nanophotothermal agent for synergistic photothermal–immunotherapy

Photothermal therapy (PTT) has attracted considerable attention in cancer treatment due to its noninvasive nature and lack of drug resistance. However, conventional photothermal agents often exhibit poor tumor accumulation, nonspecific thermal damage, and limited monotherapy efficacy, hindering their clinical translation. To overcome these constraints, we developed a tumor-microenvironment-adaptive peptide-based nano-photothermal agent (EIM^SeO-IR783) founded on the principle of intermolecular coupling-induced supramolecular photothermal effects, and integrated it with a STING agonist for synergistic photothermal-immunotherapy. The nano-photothermal agent employs a redox-responsive peptide containing selenomethionine residues as a self-assembled skeleton, and realizing the transformation from nanoparticles to nanofibers through redox, thereby regulating the aggregation state of IR783 and inducing the formation of H-aggregates. These H-aggregates enhance non-radiative energy dissipation, leading to improved photothermal conversion efficiency and photostability. In the tumor microenvironment, overexpressed GSH drives adaptive morphological transformation, enabling precise in situ heat generation and improving tumor retention and ablation. Combined with the STING agonist, photothermal-induced immunogenic cell death promotes antigen release, dendritic cell maturation, and T-cell infiltration, eliciting a robust systemic immune response for synergistic photothermal-immunotherapy. This work proposes a tumor-microenvironment-guided strategy for constructing peptide-based photothermal systems, offering a new avenue for precise cancer therapy with controllable photothermal performance and immune synergy. STATEMENT OF SIGNIFICANCE: Photothermal therapy is a promising cancer treatment, but its effectiveness is limited by poor tumor accumulation, nonspecific heating, and insufficient therapeutic outcomes. This study presents a tumor-microenvironment-adaptive peptide-based nanophotothermal agent that undergoes structural transformation in response to intracellular glutathione, enabling localized heat generation and improved tumor retention. The adaptive assembly regulates H-aggregate formation of IR783, enhancing photothermal efficiency and stability. In combination with a STING agonist, the system induces immunogenic tumor cell death and stimulates systemic antitumor immunity, achieving synergistic photothermal-immunotherapy. This work introduces a peptide-guided strategy for controlling photothermal performance within tumors and provides a versatile platform for developing precise and multifunctional biomaterial-based cancer therapies.