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.
Giovanni Germano (Sun,) studied this question.
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