LAUSR

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. Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.