Spatiotemporally programmed nanomedicine engineering to resolve conflicting immunosignals in triple-negative breast cancer

In triple-negative breast Cancer (TNBC), chemotherapy-induced immunogenic cell death (ICD) often fails to trigger truly effective antitumor immunity. This failure primarily stems from the simultaneous release of damage-associated molecular patterns (DAMPs) and immunosuppressive prostaglandin E2 (PGE₂), creating an intrinsic NOT-AND signaling conflict. This barrier hinders efficient immune priming, a response rarely induced by conventional chemotherapy. To address this conflict while minimizing toxicity, R-Gem@Cel-PV, a spatiotemporally programmed nanovesicle, was designed to impose both spatial localization and sequential signal control within the tumor microenvironment. Following preferential accumulation in tumor tissue, enzymatic disassembly of the nanomedicine triggers the rapid release of celecoxib to suppress local PGE₂ signaling and alleviate immune suppression. Subsequently, the delayed activation of a phospholipid-gemcitabine prodrug induces DAMP-releasing cell death. This temporal decoupling-unachievable with free drug combinations-converts gemcitabine from a weak ICD inducer into a potent one. In TNBC models, R-Gem@Cel-PV boosted dendritic cell maturation, orchestrated a robust antitumor immune response, and significantly inhibited both primary tumor growth and metastasis. These findings demonstrate that resolving the immunosignal conflict through precise spatiotemporal control is essential for effective immune engagement in TNBC and offer a generalizable strategy for reprogramming the immune response to chemotherapy in immune-refractory tumors.