Optimizing Immunotherapy Combined With Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

Inclusion Criteria:

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

2. Pathologically confirmed rectal adenocarcinoma with immunohistochemical resultsindicating 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, andmeeting 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; ④cT4; ⑤ MRF+ (mesorectal fascia involvement); ⑥ EMVI+ (extramural vascularinvasion);

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 (excludingpalliative colostomy), chemotherapy, or other antitumor therapies from diagnosis toenrollment;

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 otherinvestigational 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-infectiouspneumonitis;

4. Risk factors for bowel perforation, such as active diverticulitis, intra-abdominalabscess, gastrointestinal (GI) obstruction, abdominal carcinomatosis, or other knownpredisposing conditions;

5. History of other malignancies, except for cured non-melanoma skin cancer or cervicalcarcinoma in situ;

6. Active infection, heart failure, myocardial infarction within 6 months, unstableangina, or uncontrolled arrhythmia;

7. Physical examination findings or clinical laboratory abnormalities deemed by theinvestigator 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, orhistory of organ/stem cell transplantation;

10. Active hepatitis B (HBV-DNA ≥2000 U/mL), hepatitis C (HCV), or active tuberculosisinfection;

11. Prior administration of cancer vaccines or receipt of any vaccine within 4 weeksbefore treatment initiation (Note: Seasonal inactivated influenza vaccines arepermitted; live-attenuated intranasal vaccines are prohibited);

12. Concurrent use of immunomodulators, chemotherapy, investigational drugs, orlong-term corticosteroids (≥10 mg/day prednisone equivalent);

13. Patients with psychiatric disorders, substance abuse, or social circumstances thatmay compromise compliance, as assessed by the investigator;

14. Hypersensitivity or contraindications to the study medications.