ICIs in Locally Advanced Rectal Cancer- Gut | Feb. 2026

Introduction

Locally advanced rectal cancer (LARC; stage II–III) has traditionally been treated with neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision (TME). While effective for local control, this pathway often delivers modest complete response rates and exposes many patients to long-term bowel, urinary, and sexual dysfunction—especially those with low rectal tumors where a stoma risk and quality-of-life trade-offs are substantial.

In parallel, immune checkpoint inhibitors (ICIs) have rapidly shifted the landscape for the dMMR/MSI-H subtype—where deep responses can enable organ preservation in selected patients—while combination strategies (ICI + CRT/TNT) are being explored for pMMR/MSS disease. This Chinese Society of Colorectal Surgery (CNSCRS) consensus provides practical standards for who to treat, how to treat, how to assess response, and how to follow patients, with a strong emphasis on perioperative safety and organ-sparing pathways.

Why was this guidance required?

Evidence in LARC has expanded quickly over the last ~5 years, with multiple phase 2 programs and evolving real-world practice—particularly around non-operative management after complete response.

The “new bottleneck” is no longer whether ICIs work in dMMR/MSI-H disease, but how to operationalise testing, MDT decision-making, response assessment (including pseudoprogression), and safe perioperative management.

For pMMR/MSS LARC, enthusiasm for adding ICIs to CRT/TNT is growing, but benefit is heterogeneous, and toxicity attribution is complex—needing standardisation.

Key takeaways (Guidance distilled for clinicians)

A. Diagnostics and decision-making (Foundational steps)

Test MMR/MSI in all LARC before treatment—this is the gateway decision for immunotherapy strategy and Lynch screening.

Preferred testing approach: IHC for MMR proteins + PCR for MSI (with validated panels); use certified labs where possible.

Do not assume dMMR ≡ MSI-H in every case—discordance exists; dual testing can prevent missed eligibility.

Manage LARC with ICIs through a formal MDT (surgery, medical oncology, radiation, radiology, pathology ± gastroenterology/pharmacy) and adjust strategy dynamically as response evolves.

B. dMMR/MSI-H LARC (where immunotherapy is most established)

Neoadjuvant ICI is a core strategy for stage II–III dMMR/MSI-H LARC; response depth can be substantial and may enable organ preservation in selected patients.

Practical rhythm endorsed: treat → assess at ~3 months; if not at a complete clinical response, consider continuing ICIs and reassessing rather than rushing to surgery (with vigilance for non-responders).

Organ preservation (watch-and-wait) becomes a realistic goal for motivated mid/low rectal dMMR/MSI-H patients who achieve a robust clinical complete response after adequate ICI exposure.

This guidance places strong weight on structured surveillance during watch-and-wait to detect regrowth early (because salvage surgery must remain feasible).

If the response is incomplete at ~6 months in a patient seeking organ preservation, the document supports CRT as a “rescue/bridge” strategy in selected high-risk settings, with watch-and-wait still possible if a complete response is achieved after CRT.

Pseudoresidual disease/pseudoprogression is real after ICIs: imaging may overcall residual tumour; decisions should integrate endoscopy, MRI, biopsy, and MDT judgment.

Adjuvant therapy after neoadjuvant ICI is not standardised; if a patient achieves pathological complete response, observation is reasonable; if residual disease persists, options include continuing the same regimen or switching to standard adjuvant chemotherapy—best individualised.

C. pMMR/MSS (or unknown status) LARC (where combinations are exploratory)

ICI monotherapy is not a reliable strategy for pMMR/MSS LARC; the guidance focuses on combinations (ICI + CRT/TNT/SCRT) rather than ICI alone.

For pMMR/MSS LARC, the consensus supports considering LCRT + 3–6 cycles of ICI (concurrent or sequential) before TME in selected settings, recognising evidence is still largely phase 2 and heterogeneous.

For higher-risk disease or technically challenging rectal preservation, TNT + ICI is a reasonable consideration (ideally in trials), with careful monitoring for cumulative toxicity.

SCRT-based pathways (SCRT → chemo + ICI) are presented as another acceptable neoadjuvant option, with a practical cap that total immunotherapy duration generally should not exceed ~6 months in these perioperative constructs.

Organ preservation in pMMR/MSS should be approached more cautiously than in dMMR/MSI-H; if a true clinical complete response occurs, watch-and-wait can be considered, but patients must be counselled that cCR is less predictable.

Dual checkpoint blockade (PD-1 + CTLA-4) is not recommended routinely for pMMR/MSS neoadjuvant/organ-sparing therapy outside trials due to limited efficacy evidence and toxicity concerns.

D. Local excision and organ preservation pathways

After neoadjuvant ICI-based therapy, local excision can be an organ-sparing option in carefully selected downstaged cases (typically small residual disease), but must be MDT-led with clear salvage plans and high-quality pathology.

E. Safety and perioperative management (non-negotiable)

Implement baseline screening + active monitoring for immune-related AEs; the guidance flags myocarditis and pneumonitis as rare but high-risk entities requiring early detection systems.

Surgery is generally advised after irAEs have recovered to ≤ grade 1, with enhanced perioperative vigilance; an MDT model for irAE management improves diagnostic speed and consistency.

Practice-changing or confirmatory?

Practice-changing for dMMR/MSI-H LARC (selected patients): This consensus operationalises a real shift: biomarker-first rectal cancer, where dMMR/MSI-H disease can be routed toward ICI-driven organ preservation pathways in experienced centres. The direction of travel is consistent with transformative response signals seen with PD-1 blockade in dMMR rectal cancer.

More confirmatory / still-evolving for pMMR/MSS LARC: For MSS disease, this guidance is best read as a structured framework for carefully selected use (preferably trial-enriched) rather than a universal new standard, because long-term survival data and regimen-to-regimen comparisons remain unsettled.

Compared with landmark trials

MSK dostarlimab (dMMR LARC): The landmark signal that dMMR rectal tumours can achieve profound responses with PD-1 blockade underpins the organ-preservation ambition reflected in this consensus.

OPRA (TNT → selective watch-and-wait): OPRA established a modern framework for response-adapted non-operative management after neoadjuvant therapy, showing that structured surveillance and salvage can be oncologically acceptable in well-managed systems—this consensus essentially extends that philosophy into the immunotherapy era (especially for dMMR).

NRG-GI002 / pembrolizumab + TNT (mostly MSS): This program highlights the mixed and evolving nature of adding immunotherapy in unselected LARC—supporting the consensus’ cautious tone for pMMR/MSS strategies and its emphasis on trials and careful toxicity attribution.

Controversies & unanswered questions

What is the “minimum effective duration” of neoadjuvant PD-1 therapy for durable organ preservation in dMMR LARC? (6 months is common, but precision remains uncertain.)

How should we define and validate cCR after ICIs? Imaging and endoscopic findings can be misleading due to immune infiltration/fibrosis; standardised response criteria are still maturing.

Long-term oncologic safety of watch-and-wait after ICIs: early outcomes are excellent in series, but large, long follow-up datasets are still limited.

Best regimen for pMMR/MSS LARC: Which combination (LCRT+ICI vs SCRT+chemo+ICI vs TNT+ICI), which sequencing, and which patients truly benefit remains an open field.

Biomarkers beyond MSI/MMR (microbiome, immune microenvironment, novel checkpoints) are promising but not ready for routine perioperative decision-making.

Bottom line for clinicians

This Gut 2026 CNSCRS consensus converts a fast-moving evidence base into a workable clinical playbook: test MSI/MMR upfront, decide in MDT, use ICIs decisively in dMMR/MSI-H LARC (including structured organ preservation when cCR is achieved), and approach pMMR/MSS strategies with selection, vigilance, and trial-minded discipline.