NIR-II Imaging-Guided Phototherapy-Induced Senescence Reprograms Immunosuppressive Tumor Microenvironment for Potent Cancer Immunotherapy.

Abstract

Cellular senescence, characterized by irreversible cell-cycle arrest, is increasingly recognized as a pivotal mechanism in tumor suppression through regulating the tumor microenvironment (TME). Nevertheless, strategies that exploit senescence inducers to promote senescence-associated secretory phenotypes (SASPs) expression and thereby enhance immune infiltration remain underexplored. In this work, we present a phototherapy-based senescence induction approach to overcome the immunosuppressive TME in triple-negative breast cancer. We developed a reactive oxygen species-responsive nanoplatform that co-delivers a second near-infrared emissive phototheranostic molecule with aggregation-induced emission characteristics and the Aurora kinase inhibitor alisertib. Upon exposure to an 808 nm laser, the appropriate phototherapy induces alisertib release and oxidative stress, resulting in irreversible growth arrest and senescence. This process augments the secretion of immunostimulatory SASPs while suppressing tumor-promoting factors. The nanodrug remodels the TME by activating cytotoxic T lymphocytes and depleting both myeloid-derived suppressor cells and regulatory T cells, producing efficient tumor regression. Importantly, it establishes durable immunological memory, preventing postoperative recurrence without systemic toxicity. By integrating phototherapy-enhanced drug delivery with SASP-driven immunosurveillance, our study introduces senescence induction as a promising paradigm for next-generation photoimmunotherapy.