A Tumor Acidity‐Driven Transformable Nanomaterial Mediated Activation of Antigen‐Presenting Cells for Cancer Photoimmunotherapy

ABSTRACT Effective combination therapy requires targeted co‐delivery of multiple therapeutic agents via a well‐defined and controllable assembly mechanism, which most reported strategies struggle to achieve. In this study, we designed a tumor acidity‐driven transformable nanoparticle self‐assembly using a drug‐conjugated amphiphilic polymer (mPEG‐PLA‐Ce6), an acidity‐sensitive polymer (PAEMA), and the CSF‐1R inhibitor, sotuletinib (BLZ‐945), by regulating the pKa and ratio of the acidity‐sensitive material (denoted as Ce6 SNP/B). The obtained tumor acidity‐driven transformable Ce6 SNP/B released BLZ‐945 to deplete immunosuppressive M2‐type tumor‐associated macrophages predominantly localized in the perivascular regions of blood vessels. Simultaneously, tumor acidity‐driven size shrinkage of Ce6 SNP/B facilitated the deep penetration and tumor accumulation of photosensitizer Ce6 to enhance phototherapy, resulting in enhanced immunogenic cell death of tumor cells. Additionally, the acidity‐sensitive material PAEMA has the potential to induce dendritic cell maturation. Thereby, the tumor acidity‐driven transformable Ce6 SNP/B achieved cancer photoimmunotherapy by targeting tumor cells and activating antigen‐presenting cell‐mediated anti‐tumor immune effect.