This study explores the key clinical issues in the field of neoadjuvant therapy for locally advanced rectal cancer. There are three core problems with the currently recommended total neoadjuvant therapy (TNT) in the guidelines: the lack of evidence-based consensus on the timing of radiotherapy and chemotherapy, the undefined number of chemotherapy cycles, and the uncertainty in the selection of the precise radiotherapy mode. In recent years, the combination of immune checkpoint inhibitors (ICIs) with the PD-1/PD-L1 inhibitors as the core and the TNT regimen has shown a trend of further enhancing tumor regression, providing a possibility for the organ function preservation of rectal cancer. However, existing clinical studies exhibit a high degree of heterogeneity in treatment strategies. In particular, there is a lack of high-quality evidence-based medical evidence in core aspects such as the timing of ICIs intervention and the combination of treatment regimens. This study is designed as a prospective, multicenter, randomized controlled phase II study. The "pick the winner" strategy for screening the optimal regimen is adopted to evaluate the efficacy of four neoadjuvant regimens (Group SCRT-4: short-course radiotherapy → 4 cycles of chemotherapy + ICIs; Group SCRT-6: short-course radiotherapy → 6 cycles of chemotherapy + ICIs; Group LCRT-4: concurrent chemoradiotherapy → 4 cycles of chemotherapy + ICIs; Group LCRT-6: concurrent chemoradiotherapy → 6 cycles of chemotherapy + ICIs). By evaluating indicators such as the complete response rate, organ preservation rate, safety, long-term survival, as well as the anal function and quality of life of patients, treatment strategies with clinical advantages will be screened out, providing an evidence-based basis for subsequent phase III confirmatory trials.

Inclusion Criteria:

1. Age 18-75 years, regardless of gender;

2. Pathologically confirmed rectal adenocarcinoma with immunohistochemical results indicating pMMR (proficient mismatch repair) or genetic testing confirming MSS (microsatellite stability);

3. Staged as clinical stage II/III (cT3-T4N0 or cT2-4N+, no distant metastasis, per the 8th Edition AJCC Cancer Staging Manual, 2018) via MRI or endoscopic ultrasound, and meeting any one of the following:

   • cT3 with tumor inferior margin ≤ 6 cm from the anal verge;

     • cT3c/d with tumor inferior margin ≥ 6-12 cm from the anal verge; ③ cN2; ④ cT4; ⑤ MRF+ (mesorectal fascia involvement); ⑥ EMVI+ (extramural vascular invasion);

4. ECOG performance status 0-1;

5. Meeting basic laboratory criteria (e.g., hematologic, hepatic, and renal function);

6. No history of hypersensitivity to 5-Fu-based agents or platinum-based drugs;

7. Patients with primary rectal cancer must have received no prior surgery (excluding palliative colostomy), chemotherapy, or other antitumor therapies from diagnosis to enrollment;

8. No prior radiation to the planned radiotherapy site;

9. Signed informed consent form.

Exclusion Criteria:

1. Prior treatment with anti-PD-1/L1 and/or anti-CTLA-4 immunotherapy or other investigational immunotherapeutic agents;
2. History of severe autoimmune diseases, including active inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g., granulomatosis with polyangiitis);
3. Symptomatic interstitial lung disease or active infectious/non-infectious pneumonitis;
4. Risk factors for bowel perforation, such as active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal carcinomatosis, or other known predisposing conditions;
5. History of other malignancies, except for cured non-melanoma skin cancer or cervical carcinoma in situ;
6. Active infection, heart failure, myocardial infarction within 6 months, unstable angina, or uncontrolled arrhythmia;
7. Physical examination findings or clinical laboratory abnormalities deemed by the investigator to interfere with study outcomes or increase treatment-related risks, or other uncontrolled comorbidities;
8. Pregnant or breastfeeding women;
9. Congenital or acquired immunodeficiency disorders, including HIV infection, or history of organ/stem cell transplantation;
10. Active hepatitis B (HBV-DNA ≥2000 U/mL), hepatitis C (HCV), or active tuberculosis infection;
11. Prior administration of cancer vaccines or receipt of any vaccine within 4 weeks before treatment initiation (Note: Seasonal inactivated influenza vaccines are permitted; live-attenuated intranasal vaccines are prohibited);
12. Concurrent use of immunomodulators, chemotherapy, investigational drugs, or long-term corticosteroids (≥10 mg/day prednisone equivalent);
13. Patients with psychiatric disorders, substance abuse, or social circumstances that may compromise compliance, as assessed by the investigator;
14. Hypersensitivity or contraindications to the study medications.