Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy

Abstract

Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically “hot” niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)–deficient CRC required tumor cell–intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell–intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously “cold” TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell–intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.

Immunogenic PANoptosis‐Initiated Cancer Sono‐Immune Reediting Nanotherapy by Iteratively Boosting Cancer Immunity Cycle

“…The understanding of cancer immunity cycle has prompted the mechanistic exploration of initial immunomodulation that enhancing T cell adaptive immunity, such as the cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS)‐STING pathway (Figure S13, Supporting Information). [ 38 ] Evidence of DNA double‐strand breaks revealed by γ‐H2AX staining laid the foundation for activation of the cGAS‐STING signaling pathway. Since we achieved elevated PANoptosis‐mediated antigen recognition and uptake by APCs, it is rational to hypothesize that immunogenic PANoptotic cell death would activate STING in innate immune response by inducing tumor DNA release.…”

Role of STING in the treatment of non-small cell lung cancer

“…It is worth mentioning that the cGAS-STING pathway is a key pathway for activating NKs to impede the growth of T cell drug-resistant (cold) tumors [ 41 , 42 ]. Augmented STING in tumor cells reprograms the TME, rendering ‘cold ' tumors sensitive to checkpoint inhibitors, thus transforming ‘cold’ tumors into hot’ tumors, which enhances the efficacy of anti-tumor immunotherapy [ 43 ].…”