SIRT1 Inhibits T-cell Infiltration and Tertiary Lymphoid Structure Formation to Promote Radioimmunotherapy Resistance.

UNLABELLED: Microsatellite stable (MSS) rectal cancer exhibits intrinsic resistance to immunotherapy. Although radiotherapy is frequently combined with immune checkpoint inhibitors (ICI) to augment immunotherapy responses, numerous immunologically cold tumors remain unresponsive. In this study, we observed a significant increase in electron transport chain activity, acetyl-CoA levels, and global lysine acetylation levels in patients achieving a pathologic complete response following immunotherapy administered after radiotherapy. Transcriptomic screening and in vivo experiments revealed that SIRT1, a key regulator of protein acetylation, restricted the immunostimulatory effects of radiotherapy. Mechanistically, SIRT1 deacetylated DDX5, promoting the unwinding of irradiation-induced R-loops and inhibiting the accumulation of cytoplasmic RNA:DNA hybrids to suppress cGAS/STING pathway activation and T-cell infiltration. Moreover, radiotherapy induced a tryptophan-SIRT1-SLC36A4 positive feedback loop that enhanced SIRT1 activity and promoted competitive tryptophan uptake from the microenvironment, thereby inhibiting tertiary lymphoid structure (TLS) formation and radioimmunotherapy efficacy. Finally, combining both an SIRT1 inhibitor and aspirin with radiotherapy converted ICI-unresponsive rectal cancer into immunogenic tumors that were sensitive to ICI. Together, this study identifies SIRT1 as a potential biomarker and therapeutic target to overcome radioimmunotherapy resistance in MSS rectal cancer.

SIGNIFICANCE: Radiotherapy activates a tryptophan-SIRT1 metabolic feedback loop in microsatellite stable rectal cancer that suppresses T cell infiltration and tertiary lymphoid structures formation, which can be overcome with SIRT1 inhibition and aspirin.