Autophagy-Modulated Sonodynamic Therapy Triggers Mitochondrial Catastrophe for Potent Immunogenic Tumor Eradication

Sonodynamic immunotherapy represents a promising strategy for cervical cancer treatment by stimulating antitumor immune responses. However, therapy-induced prosurvival autophagy may attenuate therapeutic efficacy. To address this limitation, we constructed multifunctional nanoparticles (poly[lactic- co -glycolic acid]-b-poly[ethylene glycol] [PLGA-PEG _2,000 ]-based nanoparticles coloaded with hematoporphyrin monomethyl ether and SAR405 [PHS NPs]) codelivering the sonosensitizer hematoporphyrin monomethyl ether and the selective vacuolar protein sorting 34 inhibitor SAR405. Upon low-intensity focused ultrasound irradiation, PHS NPs generated reactive oxygen species that induced mitochondrial stress while concurrently modulating autophagic flux through VPS34 inhibition. This coordinated intervention was associated with microtubule-associated protein 1A/1B–light chain 3-II and p62 coaccumulation and the presence of undegraded autolysosomal structures, suggesting impairment of lysosome-associated autophagic degradation. Enhanced oxidative stress, together with modulation of autophagic flux, was accompanied by lysosomal dysfunction and reduced degradative capacity. These alterations were associated with sustained intracellular stress and amplified oxidative injury in tumor cells. Functionally, the combined treatment suppressed tumor growth, promoted immunogenic cell death, and was accompanied by macrophage polarization toward an M1-like phenotype and increased CD8 ⁺ T cell infiltration. Validated in HPV-associated tumor models, this nanoparticle-based strategy provides a rational and potentially translatable platform to mitigate autophagy-associated adaptive responses and enhance the therapeutic potential of sonodynamic immunotherapy in solid tumors.