Abstract The majority (up to 85%) of colorectal cancer (CRC) patients have a microsatellite stable (MSS) tumor phenotype, which is a poor responder to immune checkpoint blockade (ICB). Therefore, there is a need to identify novel checkpoints in the tumor microenvironment, such as ST2 (Stimulation 2, IL33 receptor). We demonstrated ST2 to be prominently expressed on human tumor cells, especially MSS tumors, through multiplex immunofluorescence staining of CRC patient samples and publicly available datasets. Using CRC patient-derived organoids, we established that activation of tumoral IL33/ST2 signaling conferred tumor cell protection from T cell-mediated killing. To investigate the mechanistic basis of how tumor cells escape T cell killing, we used colonoscopy-induced, orthotopic murine tumors. We uncovered that IL33/ST2 signaling reduced antigen presentation, driven by reduced immunoproteasome activity. Removing tumoral ST2 signaling using CRISPR/Cas9-gene editing leads to significant tumor growth control and increased infiltration of T cells with a reduced terminally exhausted phenotype. Altogether, these findings indicate ST2 as a potential, novel checkpoint target on tumor cells to enlarge the pool of patients benefiting from ICB. Citation Format: Alyssa Mauri Cornista, Tao Yu, Zhuolong Zhou, Nikša Roki, Alberto Sigler, David M. Suissa, Haniyeh Eyvani, George E. Sandusky, Rimpi Khurana, Yan Guo, Molly Dalzell, Shyamananda Singh Mayengbam, Prasenjit Dey, Christine Rafie, Erietta Stelekati, Jashodeep Datta, Saratchandra S. Khumukcham, Jatin Roper, Nivedh Paluvoi, Sandro Satta, Daniel Bilbao Cortes, Alejandro Villarino, Kevin Van der Jeught. Tumoral IL-33/ST2 signaling drives immune escape through reduced antigen presentation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2799.
Cornista et al. (Fri,) studied this question.