Background: Total neoadjuvant therapy (TNT) has become the standard of care for locally advanced rectal cancer (LARC), achieving pathological complete response (pCR) rates of 15%–30%. Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 antibodies, have shown remarkable efficacy in mismatch repair–deficient tumours. Whether adding ICIs to TNT can improve outcomes in proficient mismatch repair (pMMR)/microsatellite stable (MSS) LARC remains an area of active investigation. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of TNT combined with ICIs compared with standard neoadjuvant therapy in LARC.
Methods: We searched PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science from inception through March 2026 for randomised controlled trials comparing neoadjuvant therapy with ICIs versus without ICIs in LARC. The primary outcome was the complete response (CR) rate, encompassing pCR and clinical complete response. Risk ratios (RRs) were pooled using a DerSimonian–Laird random-effects model. Heterogeneity was assessed with the I² statistic. Subgroup analyses were performed by radiotherapy type (short-course radiotherapy (SCRT) versus long-course radiotherapy (LCRT)). Risk of bias (RoB) was evaluated using the Cochrane RoB 2.0 tool, and certainty of evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. The review was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.
Results: Five randomised trials (N = 1,070; ICI arm = 429; control arm = 437) met inclusion criteria. Adding ICIs to neoadjuvant therapy significantly increased the CR rate (pooled RR 1.72, 95% confidence intervals (CI) 1.32–2.25; p < 0.001). Heterogeneity was moderate (I² = 44.8%). Subgroup analysis revealed a greater benefit with SCRT-based regimens (RR 2.01, 95% CI 1.56–2.58; I² = 0%) compared with LCRT-based regimens (RR 1.33, 95% CI 0.88–2.01; I² = 39.5%). Leave-one-out sensitivity analyses confirmed the robustness of the pooled estimate. No significant publication bias was detected (Egger’s test p = 0.84). Additionally, eight single-arm TNT + ICI studies in pMMR/MSS LARC reported pCR rates of 37%–73%, consistently exceeding historical TNT benchmarks. The GRADE certainty of evidence was moderate, downgraded for indirectness.
Conclusion: The addition of ICIs to neoadjuvant therapy significantly improves CR rates in LARC, with the greatest benefit observed when ICIs are combined with SCRT-based TNT. These findings support the integration of ICI into TNT as a strategy to enhance organ preservation opportunities. Long-term survival data from ongoing phase III trials are needed to confirm that these short-term benefits translate into durable oncologic outcomes.
