Baseline tumor features and peripheral blood immune dynamics that underlie efficacy in MSS metastatic colorectal cancer treated with regorafenib, ipilimumab, and nivolumab [Blood]

Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies, yet in a phase I trial the combination of regorafenib, ipilimumab, and nivolumab (RIN) demonstrated a 27.6% overall response rate and a median overall survival of 20 months, particularly benefiting patients without liver metastases. Correlative studies of tumor biopsies from eight patients and peripheral blood samples from 29 patients revealed that good responders had a more immunogenic tumor microenvironment (TME) at baseline, with enhanced cellular proliferation, active DNA repair pathways, and elevated STING pathway expression, along with a Th1-skewed cytokine profile in peripheral blood. Poor responders exhibited dysregulated inflammation, vascular remodeling, and T cells showing pathogen-response gene signatures indicative of chronic inflammation; in those with liver metastases, T cells showed immune senescence and metabolic hyperactivation. After RIN therapy, good responders displayed increased TME immune cell infiltration, upregulation of immune-related genes, marked expansion of previously low-frequency TCR clones in CD8 T cells, heightened naive T cell proliferation, and activation of immune and metabolic pathways. Poor responders initially showed transient increases in bulk CD8 T cells, NK cells, Th1 cytokine production, and reduced exhaustion markers but did not sustain meaningful TCR repertoire expansion. These findings underscore the potential of RIN to reshape the immunological landscape of MSS mCRC by modulating both TME and systemic immunity, highlighting the importance of predictive biomarkers to guide personalized therapeutic strategies, particularly for overcoming resistance in liver metastases.