Efficacy and Safety of Immune Checkpoint Inhibitor-Based Neoadjuvant Therapy Combinations in Proficient Mismatch Repair/Microsatellite Stable Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis.

Neoadjuvant immunotherapy has shown remarkable efficacy in mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) locally advanced rectal cancer (LARC), whereas mismatch repair-proficient/microsatellite stable (pMMR/MSS) tumors have historically been resistant because of an immunosuppressive tumor microenvironment. Recently, immune checkpoint inhibitor (ICI)-based combinations with chemoradiotherapy or total neoadjuvant therapy have shown encouraging activity in pMMR/MSS LARC, though their efficacy, safety, and optimal design remain unclear. PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and major conference proceedings were searched for trials evaluating neoadjuvant ICI-based therapy in pMMR/MSS LARC. The primary endpoint was pathological complete response (pCR), with major pathological response (MPR), clinical complete response (cCR), sphincter-preserving surgery (SPS), and adverse events as secondary endpoints. Data were synthesized using single-arm, pairwise, and network meta-analytical approaches to evaluate the efficacy, safety and relative treatment rankings. Twenty-nine studies (1865 patients) were included. Pooled pCR, MPR, cCR, and SPS rates were 34%, 62%, 32%, and 82%, respectively, while grade ≥ 3 treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) occurred in 19% and 4% of patients. Subgroup analyses indicated higher pCR with short-course radiotherapy (SCRT) and higher MPR with concurrent radioimmunotherapy. Compared with non-ICI controls, ICI-based regimens significantly improved pCR (OR 2.12) and MPR (OR 2.03) without increasing severe toxicity. The network meta-analysis ranked SCRT plus chemoimmunotherapy highest for achieving pCR (P-score = .95). ICI-based neoadjuvant therapy, particularly SCRT plus chemoimmunotherapy, shows promising efficacy without a significant increase in severe toxicity in pMMR/MSS LARC, warranting validation in large-scale trials.