Photocontrolled nanosystem potentiates photo-chemoimmunotherapy against TNBC by integrating apoptosis/ferroptosis/ pyroptosis and STING activation

Abstract

Triple-negative breast cancer (TNBC) frequently exhibits profound chemoresistance and a highly immunosuppressive tumor microenvironment (TME), leading to suboptimal clinical outcomes with high risks of early recurrence and distant metastasis. Existing monotherapies remain inadequate in disrupting these therapeutic barriers. To overcome the aforementioned obstacles, we developed a spatiotemporally regulated organelle-targeted nanoplatform, IR820-GEM@MIL101 (IGM), Its design aims to achieve precise mitochondrial intervention and coordinate cGAS–STING-mediated immune activation. This design relies on EPR-mediated passive targeting to achieve preferential tumor accumulation, allowing IGM to accumulate specifically in tumor tissues and trigger a series of reactions in response to endogenous stimuli (acidic pH and elevated glutathione) in synergy with exogenous near-infrared laser activation, enabling controlled drug release. The platform efficiently eliminates tumor cells by inducing multiple modes of cell death, including pyroptosis, ferroptosis, and apoptosis, while simultaneously triggering immunogenic cell death (ICD) and activating the cGAS–STING pathway. This dual immunostimulatory strategy effectively converts “cold” tumors into “hot” tumors. In a bilateral tumor model, IGM treatment increased CD8+ T-cell infiltration in distal tumors by 94% and achieved a tumor inhibition rate of 92.7% in distant lesions. This work shifts the therapeutic focus from superficial multi-drug packaging to precise organelle-targeted intervention, providing a promising strategy for light-regulated combinatorial immunotherapy against aggressive malignancies.