Can Chemoradiotherapy Expand Immune Checkpoint Blockade Responsiveness in Mismatch Repair‐Proficient Rectal Cancer?

ABSTRACT Immune checkpoint blockade (ICB) has transformed the treatment of mismatch repair‐deficient (dMMR) colorectal cancer but produces no meaningful benefit in advanced mismatch repair‐proficient (pMMR) disease. In the neoadjuvant setting, however, pathological responses have been reported in a subset of pMMR tumors, suggesting that clinical context modifies apparent ICB sensitivity. In pMMR rectal cancer, adding ICB to chemoradiotherapy (CRT) has been associated with pathological complete response (pCR) rates of 30% or more in several trials, higher than expected with CRT alone. These data are clinically provocative, particularly because sustained clinical complete response (cCR) may support watch‐and‐wait, but pCR and cCR remain early endpoints; long‐term disease control and organ‐preservation safety remain insufficiently defined. Whether CRT induces ICB responsiveness remains unresolved. The increase in pCR with sequential PD‐1 blockade after CRT provides a clinical signal for testing this possibility, but pCR cannot distinguish CRT‐induced ICB responsiveness from the simple additive effects of CRT and ICB. Pretreatment T‐cell‐inflamed features are candidate enrichment markers, but none is validated for patient selection. Priorities are therefore to compare biomarkers associated with ICB responsiveness before and after CRT within the same patients and prospectively validate selection assays. Long‐term follow‐up must determine whether treatment‐induced increases in pCR are accompanied by better disease control and whether organ preservation after sustained cCR is safe.