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

Background 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. Methods 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. Results Twenty-nine studies (1,865 patients) were included. Pooled pCR, MPR, cCR, and SPS rates were 34%, 62%, 32%, and 80%, 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 and SPS 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 = 0.95). Conclusions 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.