Dual-organelle–coordinated sonodynamic nanoplatform amplifies immunogenic cell death to drive robust antitumor immunity in cold tumors

Immune-excluded “cold” tumors are characterized by dense stromal barriers, limited cytotoxic T-cell infiltration, and insufficient immunogenic cell death (ICD), which collectively restrict the efficacy of immunotherapy. Pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) represent two of the most refractory cold tumor entities, marked by pronounced desmoplasia and persistent immune exclusion. Here, we report a mitochondria–lysosome dual-organelle–enriched nanoplatform (PT2@GEM NPs) designed to amplify ICD through sonodynamically induced subcellular stress. The organic sonosensitizer PT2 is engineered for stable lysosomal retention via endo–lysosomal trafficking, while cationic structural motifs promote mitochondrial accumulation. Upon ultrasound activation, PT2@GEM NPs generate reactive oxygen species concurrently in lysosomes and mitochondria, inducing lysosomal membrane permeabilization and severe mitochondrial dysfunction, including widespread mitochondrial permeability transition pore opening and loss of membrane potential. As a result, canonical ICD hallmarks are markedly enhanced compared with single-modality treatments. In patient-derived organoids and in murine models of PDAC and TNBC, PT2@GEM NPs combined with ultrasound achieve 60–80% tumor growth inhibition, significantly outperforming chemotherapy or sonodynamic therapy alone. This treatment prolongs survival without evident systemic toxicity. Integrated transcriptomic, metabolomic, and immunological analyses reveal robust activation of inflammatory and innate immune pathways, metabolic rewiring, a 2–3-fold increase in intratumoral CD8⁺ T-cell infiltration, and a 3-fold expansion of effector memory T cells, indicating durable antitumor immune memory. This work establishes a materials-driven sonodynamic chemoimmunotherapy strategy in which rational dual-organelle targeting synchronizes intracellular stress to amplify ICD, convert immune-excluded cold tumors into CD8⁺ T cell–inflamed phenotypes, and provide a translatable nanotechnological approach for the treatment of stromal-rich malignancies.