Small-molecule photosensitizer for enhanced antiangiogenesis and immunosuppressive tumor microenvironment reprogramming in anti-metastatic photodynamic therapy.

Tumor angiogenesis, a well-recognized barrier to effective antitumor treatment, drives tumor growth, recurrence, and metastasis by facilitating tumor cell intravasation, impairing immune cell infiltration, and fostering an immunosuppressive tumor microenvironment. Herein, a small-molecule drug T-Pc was rationally designed and synthesized by covalent conjugation of the alkylating agent temozolomide (TMZ) and the photosensitizer zinc phthalocyanine (ZnPc). The dual antitumor and anti-angiogenic actions of low-dose TMZ and ZnPc augment the in vitro performance of T-Pc, conferring the conjugate with superior photocytotoxicity and potent anti-migration/anti-invasion efficacy against both tumor cells and vascular endothelial cells. Meanwhile, its significant cellular internalization and favorable tumor accumulation were validated both in vitro and in vivo. Most importantly, T-Pc-mediated photodynamic therapy (PDT) significantly suppressed primary tumor growth and pulmonary metastasis, which could be attributed to its combined vascular disruption effect, and the subsequent remodeling of the immunosuppressive tumor microenvironment. Collectively, our study provides a high-performance strategy for the efficient treatment of metastatic tumors.