Integrating Immune Checkpoint Inhibitors With Total Neoadjuvant Therapy in Proficient Mismatch Repair Rectal Cancer

The management of locally advanced rectal cancer (LARC) has evolved with the adoption of total neoadjuvant therapy (TNT), integrated chemoradiotherapy (CRT) or short-course radiotherapy (SCRT) with systemic chemotherapy. Although immune checkpoint inhibitors (ICIs) show remarkable efficacy in mismatch repair-deficient/MSI-H colorectal cancer, their role in proficient mismatch repair (pMMR)/microsatellite stable (MSS) tumors remains limited owing to poor immunogenicity. CRT or SCRT has emerged as a promising immunomodulator capable of converting "cold" pMMR/MSS tumors into "hot" immune-responsive environments, thereby enhancing antigen presentation and PD-L1 expression. Although CRT-ICI combinations have achieved modest efficacy with pathological complete response (pCR) rates generally plateauing around 40%, recent studies that incorporate ICIs into TNT (TNT-ICI), notably UNION, TORCH, and PRECAM, have achieved higher pCR and clinical complete response (cCR) rates (40%-60%). Focusing exclusively on TNT, this review underscores that optimal sequencing and chemotherapy intensity are paramount for maximizing synergy while limiting lymphodepletion. It consolidates the growing clinical evidence and mechanistic rationale for integrating ICIs into TNT, for pMMR/MSS LARC, and delineates a pathway toward higher pCR and cCR rates alongside organ-preserving treatment strategies.