An Epigenetic Nanoagonist Facilitates T Cell Priming, Recruitment, and Reinvigoration in Tumors Resistant to PD‐L1 Therapy

Abstract Inefficient priming, poor recruitment, and inadequate reinvigoration of T cells challenges the therapy of PD‐L1‐resistant tumors. Herein, a pH‐responsive charge‐reversal nanoplatform integrating coactivator‐associated arginine methyltransferase 1 (CARM1) inhibitor (iCARM1) and poliovirus receptor siRNA (siPVR) is developed. Upon tumor penetration, iCARM1 released in tumor cells facilitates T cell priming by epigenetically activating cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling‐mediated dendritic cell maturation. Meanwhile, in T cells, iCARM1 facilitates their recruitment by upregulating CXC‐chemokine receptor 3 (CXCR3) expression. The released siPVR silences pvr to reinvigorate T cells. This epigenetic nanoagonist induces a robust immune response, dramatically suppresses tumor growth, metastasis, and relapse, and confers durable protection against secondary tumor challenge. Multiple PD‐L1‐resistant models demonstrate the broad applicability of this strategy. This study thus represents an innovative approach for facilitating multilevel T cell responses to combat PD‐L1‐resistant tumors.