STING signalling compensates for low tumour mutation burden to drive anti-tumour immunity

While mutation-derived neoantigens are well recognized in generating anti-tumor T cell responses, increasing evidences highlight the complex association between tumor mutation burden (TMB) and tumor infiltrating lymphocytes (TILs). We examined this relationship across nine major cancer types to identify non-TMB determinants of immune responses within the tumor microenvironment. TMB overall correlated poorly with both TILs and exhausted CD8+ T cells (Tex) as an indicator of tumor-specific T cells. Computational clustering analysis performed on 4,510 tumors from The Cancer Genome Atlas revealed a group of tumors with abundant Tex but low TMB. In those tumors, we observed significantly higher expression of the stimulator of interferon genes (STING) signaling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumors. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation. These results highlight that TMB alone does not fully predict tumor immune profiles, with STING signaling compensating for low TMB in non-hypermutated tumors to enhance anti-tumor immunity. We further validated these findings using clinical samples via NanoString technology and single cell RNA-seq. Translating these results, STING agonists may benefit patients with non-hypermutated tumors. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unraveled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy. We employed single cell sequencing from 11 primary tumors (PTs) of patients with breast cancer (BC), including 6 ER+ and 5 triple negative BC, followed by unbiased Seurat cluster analysis to assess the STING singaling in each cell type. Additional 3 ER+ BC PT scRNA-seq data for this work have been uploaded to GSE248288.