Carrier-free nanomodulators reprogramming acetate metabolism for cancer photo-immunotherapy via c-Myc inhibition-induced closed-loop regulatory circuit

Abstract

Non-small cell lung cancer (NSCLC) remains difficult to cure owing to therapy resistance and immune evasion that limits durable therapeutic responses. Here, we report a carrier-free nanoregulator (CE NPs) formed by co-assembling chlorin e6 (Ce6) with a covalent c-Myc inhibitor (EN4), enabling photo-immunotherapy that couples photodynamic therapy (PDT)-induced immunogenic cell death (ICD) with acetate-metabolism-driven immune reprogramming. Upon 660-nm light irradiation, CE NPs efficiently generate reactive oxygen species to trigger apoptosis and subsequent ICD. In parallel, EN4-mediated c-Myc suppression coordinately downregulates MCT1, Cyclin D1, LDHA, and PD-L1, thereby interrupting the MCT1/acetate/acetyl-CoA/c-Myc self-amplifying “closed-loop” circuit, restraining tumor proliferation and glycolysis, and alleviating PD-L1-associated immune escape. Consequently, CE NPs, along with 660-nm light illumination, achieve robust tumor growth inhibition without obvious systemic toxicity under the tested conditions, promotes systemic immune activation, suppresses distant tumors in a bilateral model, and establishes durable immune memory that resists tumor rechallenge. Collectively, this work establishes a “closed-loop regulatory circuit” strategy by integrating PDT-induced ICD with acetate-metabolism reprogramming to overcome immune evasion and improve NSCLC photo-immunotherapy.