Node-Sparing Short-Course Radiotherapy Sequential Chemotherapy and PD-1 Inhibitor for Mid/Low pMMR/MSS Rectal Cancer (MODIFI-RC-II)

Inclusion Criteria:

• • Voluntarily signs a written informed consent form.

• Aged between 18 and 75 years at the time of enrollment.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Expected survival of more than 2 years.

• Histologically confirmed rectal adenocarcinoma.

• Tumor biopsy indicates proficient mismatch repair (pMMR), defined by positiveimmunohistochemical staining for MSH1, MSH2, MSH6, and PMS2, or moleculartesting confirms microsatellite stability (MSS).

• Clinical stage T3-4N0M0 or TanyN+M0 based on the 8th edition of the AJCC TNMclassification, as evaluated by high-resolution MRI ± endoscopicultrasound/transrectal ultrasonography, with the tumor located in themid-to-lower rectum below the peritoneal reflection.

• Prior to enrollment, a qualified surgical attending physician must assess thepatient's medical history and confirm eligibility for curative R0 resection.

• No prior systemic or local anti-tumor treatment for rectal cancer, includingradiotherapy, chemotherapy, immunotherapy, biologics, or small-moleculetargeted therapy.

• Agrees to provide tumor tissue and peripheral blood samples during screeningand throughout the study for research purposes.

• Adequate organ function, defined as follows:

• Hematologic (without use of blood components or growth factors within 7 daysprior to treatment initiation):

• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L

• Platelet count ≥ 100 × 10⁹/L

• Hemoglobin ≥ 90 g/L

• Renal:

• Calculated creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gaultformula:

CrCl (mL/min) = [(140 - age) × weight (kg) × 0.85 (if female)] / (72 × serum creatinine [mg/dL])

• Urine protein < 2+ on dipstick or < 1.0 g per 24-hour collection

• Hepatic:

• Total bilirubin ≤ 1.5 × ULN

• AST and ALT ≤ 2.5 × ULN

• Serum albumin ≥ 28 g/L

• Coagulation:

• INR and APTT ≤ 1.5 × ULN

• Cardiac:

• Left ventricular ejection fraction (LVEF) ≥ 50%

• Women of childbearing potential must have a negative urine or serum pregnancy testwithin 3 days prior to initiating study treatment. If the urine test isinconclusive, a serum test must confirm the negative result. Women of childbearingpotential who are sexually active with non-sterilized male partners must agree touse highly effective contraception from screening through 120 days after the lastdose of study drug. The need for continued contraception beyond this period shouldbe discussed with the investigator.

• Women of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) and havenot undergone menopause (defined as ≥12 months of amenorrhea without alternativemedical cause, with FSH levels in the postmenopausal range).

• Highly effective contraception methods are those with <1% failure rate per year whenused consistently and correctly (e.g., hormonal contraceptives). In addition tobarrier methods, hormonal contraception is required. Periodic abstinence and thecalendar method are not considered acceptable.

• Willing and able to comply with scheduled visits, treatment plans, laboratory tests,and other study requirements.

Exclusion Criteria:

• • Presence of suspected metastatic lesions or unresectable locally advanced disease,regardless of clinical stage.

• History of any other malignancy within 5 years prior to enrollment, excludingthose considered cured by local therapy (e.g., basal cell carcinoma, squamouscell carcinoma of the skin, superficial bladder cancer, or ductal carcinoma insitu of the breast).

• Lesions initially staged as T1N0 eligible for local excision, or T2N0 suitablefor sphincter-preserving surgery after multidisciplinary discussion.

• Evidence of acute conditions requiring emergency surgery, such as bowelobstruction, perforation, or gastrointestinal bleeding.

• Synchronous multiple primary rectal cancers.

• History of pelvic or abdominal radiotherapy.

• Inability to swallow tablets, malabsorption syndrome, or any conditionaffecting gastrointestinal absorption.

• Prior systemic or local anti-tumor therapy for locally advanced rectal cancer,including curative surgery, chemotherapy, radiotherapy, immunotherapy (e.g.,immune checkpoint inhibitors, agonists, or cell-based therapies), biologics, orsmall-molecule targeted therapy.

• Use of nonspecific immunomodulatory treatments (e.g., interleukins,interferons, thymic peptides, tumor necrosis factor) within 2 weeks prior tostudy treatment (excluding IL-11 for thrombocytopenia), or use of herbal ortraditional Chinese medicines with anti-tumor indications within 1 week priorto treatment.

• Active autoimmune disease requiring systemic treatment (e.g., withdisease-modifying drugs, corticosteroids, or immunosuppressants) within thepast 2 years. Replacement therapies (e.g., thyroid hormone, insulin, orphysiological corticosteroids for adrenal or pituitary insufficiency) are notconsidered systemic treatments.

• History of or current interstitial lung disease or non-infectious pneumonitisrequiring systemic corticosteroid treatment.

• History of bleeding disorders or coagulopathy; patients requiring long-termanticoagulation (e.g., atrial fibrillation with CHADS2 score ≥ 2).

• Uncontrolled comorbidities, including but not limited to: decompensatedcirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe pepticulcer or gastritis, or psychiatric/social conditions affecting compliance orconsent.

• History of myocarditis, cardiomyopathy, or malignant arrhythmias; unstableangina, heart failure requiring hospitalization, or vascular disease (e.g.,aortic aneurysm requiring repair or deep vein thrombosis) within 12 monthsprior to study treatment; other cardiac conditions impacting safety (e.g.,poorly controlled arrhythmia, myocardial infarction, or ischemia).

• Within 6 months prior to treatment: history of gastroesophageal varices, severeulcers, non-healed wounds, gastrointestinal perforation, fistulas, bowelobstruction, intra-abdominal abscess, or acute GI bleeding.

• Arterial thromboembolism, grade ≥3 venous thromboembolism (per NCI-CTCAE v5.0),transient ischemic attack, stroke, hypertensive crisis, or hypertensiveencephalopathy within 6 months prior to study treatment.

• Acute exacerbation of COPD within 1 month prior to treatment; currenthypertension not controlled to <160/100 mmHg despite antihypertensivemedication.

• Active or prior inflammatory bowel disease (e.g., Crohn's disease, ulcerativecolitis) or chronic diarrhea.

• Severe infections within 4 weeks prior to treatment, including complicationsrequiring hospitalization, sepsis, or severe pneumonia; active infectionsrequiring systemic anti-infective therapy within 10 days prior to treatment (excluding antiviral therapy for HBV or HCV).

• Major surgery or serious trauma within 30 days prior to treatment; minor localsurgery within 3 days (excluding PICC placement).

• History of immunodeficiency or HIV antibody positivity; long-term systemiccorticosteroid or immunosuppressive therapy.

• Active tuberculosis or suspected TB not ruled out via clinical assessment (e.g., sputum test, chest X-ray); known active syphilis.

• History of allogeneic organ or hematopoietic stem cell transplantation.

• Untreated active hepatitis B (HBsAg-positive with HBV DNA > 1,000 copies/mL or 200 IU/mL); active hepatitis C (HCV antibody-positive with detectable HCV RNA).

• Receipt of a live vaccine within 30 days prior to treatment or planned livevaccination during the study.

• Known hypersensitivity to any component of the investigational drugs, orhistory of serious hypersensitivity reactions to monoclonal antibodies.

• Known history of psychiatric disorders, substance abuse, alcoholism, or drugaddiction.

• Pregnant or breastfeeding women.

• Any disease, treatment, or abnormal laboratory finding that may interfere withstudy results, affect full study participation, or is not in the patient's bestinterest.

• Systemic or local disease caused by a benign tumor, or tumor-relatedcomplications/symptoms that pose high medical risk or survival uncertainty (e.g., leukemoid reaction with WBC > 20 × 10⁹/L, cachexia with >10% weight lossin 3 months prior to screening, or BMI ≤18).