A subset of MMR-proficient colon cancers responds to neoadjuvant immunotherapy.

Mismatch repair-proficient (pMMR) colorectal cancers (CRC) have long been considered nonresponsive to immune checkpoint blockade (ICB), in contrast to their mismatch repair-deficient (dMMR) counterparts. Recent evidence indicates that neoadjuvant immunotherapy can be used to treat pMMR CRC before surgery, potentially reducing postoperative relapse. Tan et al. report results from the NICHE-2 trial, which achieved a 26% response rate in early-stage pMMR colon cancer (CC) patients. Molecular studies show that despite low tumor mutational burden (TMB), responders exhibit higher chromosomal instability (CIN), TP53 mutations, and enrichment of proliferative and cell-cycle signatures, associated with higher density of Ki-67+ tumor and CD8+ T cells. In contrast, nonresponders display metabolic and stromal reprogramming, enhanced TGF-β signaling, and immune exclusion. Circulating tumor DNA (ctDNA) clearance correlated with pathological response and long-term disease-free survival postsurgery. While the biological and molecular determinants underlying the response rates observed in the NICHE-2 trial remain to be fully elucidated, the work by Tan et al. suggests that biomarker-guided neoadjuvant immunotherapy could represent a valuable strategy to achieve pathological responses in early-stage pMMR CC, despite its clinical relevance requiring further evaluation.