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Significance Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive. Self-specific CD8+ T cells are particular characteristics of tumor types with lower tumor mutation burden and poorer outcomes. Unlike foreign-specific T cells, they have been curiously resistant to stimulation with cognate antigens. We developed an innate immunity-stimulating nanoparticle to activate tumor-infiltrating CD8+ T cells recognizing both self- and neoantigens in a potent yet safe manner. This resulted in effective tumor growth inhibition or elimination in two murine tumor models and the activation of endogenous T cells in patient-derived tumor organoids across three cancer types. This strategy represents a promising pathway for broadly effective cancer immunotherapy.

Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities