In Situ STING‐Activating Nanovaccination with TIGIT Blockade for Enhanced Immunotherapy of Anti‐PD‐1‐Resistant Tumors

Abstract Immunotherapies comprising programmed cell death protein 1/PD ligand 1 (PD‐1/PD‐L1) immune checkpoint inhibitors are effective cancer treatments. However, the low response rate and immunoresistance resulting from alternative immune checkpoint upregulation and inefficient immune stimulation by T cells are problematic. The present report describes a biomimetic nanoplatform that simultaneously blocks the alternative T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT) checkpoint and activates the stimulator of interferon genes (STING) signaling pathway in situ for enhanced antitumor immunity. The nanoplatform is engineered by fusing a red blood cell membrane with glutathione‐responsive liposome‐encapsulated cascade‐activating chemoagents (β‐lapachone and tirapazamine), and anchoring them with a detachable TIGIT block peptide (named as RTLT). In the tumor environment, the peptide is spatiotemporally released to reverse T‐cell exhaustion and restore antitumor immunity. The cascade activation of chemotherapeutic agents causes DNA damage and inhibits the repair of double‐stranded DNA, which induces robust in situ STING activation for an efficient immune response. The RTLT inhibits anti‐PD‐1‐resistant tumor growth, and prevents tumor metastasis and recurrence in vivo by inducing antigen‐specific immune memory. This biomimetic nanoplatform thus provides a promising strategy for in situ cancer vaccination.