Radiotherapy Plus Iparomlimab and Tuvonralimab (QL1706), Regorafenib, and CAPOX as Neoadjuvant Therapy for pMMR/MSS LARC.

Inclusion Criteria:

1. Age: 18-75 years.
2. Pathology: Histologically confirmed rectal adenocarcinoma, with the lower tumor edge ≤12 cm from the anal verge.
3. Initial Clinical Stage: cT3-4aN0M0 or cT1-4aN+M0, regardless of MRF, EMVI, or LLNM status.

   Preoperative staging methods: chest and abdominal CT, pelvic MRI, endoscopic ultrasound (EUS), or transrectal ultrasonography.
4. pMMR/MSS Status: pMMR confirmed by immunohistochemistry (IHC) at the study center's pathology department, or MSS/MSI-L confirmed by PCR or NGS.
5. ECOG Performance Status: 0-1.
6. Informed Consent: Voluntarily agrees to participate and signs the informed consent form.
7. No Prior Treatment: No previous therapy targeting rectal adenocarcinoma, including radiotherapy, chemotherapy, or surgery.
8. Planned Surgery: Surgery is planned upon completion of neoadjuvant therapy.
9. Expected Survival: ≥6 months.
10. Adequate Organ and Bone Marrow Function, meeting all of the following (with no blood products, growth factors, or other hematopoietic-supportive medications used within 14 days before first administration):

    Hematology:

    Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L Platelet count ≥100 × 10\^9/L Hemoglobin ≥90 g/L

    Serum Biochemistry:

    Serum albumin ≥30 g/L Total bilirubin ≤1.5 × ULN ALT ≤2.5 × ULN, AST ≤2.5 × ULN Alkaline phosphatase (ALP) ≤2.5 × ULN

    Serum creatinine ≤1.5 × ULN, or creatinine clearance (CrCl) ≥50 mL/min, calculated by the Cockcroft-Gault formula:
11. Contraception:

    Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first study dose, and must use effective contraception (e.g., intrauterine device, oral contraceptive, or barrier method) during the study and for at least 120 days after the final dose.

    Male participants with partners of childbearing potential must be surgically sterile or must agree to use effective contraception during the study and for 120 days after the final dose.
12. Compliance and Follow-up: Demonstrates good compliance and agrees to attend follow-up visits.
13. Biological Samples: Agrees to provide blood, urine, stool, and tumor tissue samples.

Exclusion Criteria:

1. Active Autoimmune Disease: Any active autoimmune disease requiring systemic treatment (i.e., disease-modifying medications, corticosteroids, or immunosuppressive agents) within 2 years prior to enrollment (e.g., myasthenia gravis, systemic lupus erythematosus, interstitial pneumonitis, uveitis, ulcerative colitis, autoimmune hepatitis, hypophysitis, systemic vasculitis, nephritis, hyperthyroidism, hypothyroidism, mixed connective tissue disease).

   Exceptions: vitiligo, or childhood asthma that has fully resolved in adulthood without therapy.

   Asthma requiring bronchodilator therapy is ineligible. Physiologic replacement therapy (e.g., thyroid hormone, insulin, or low-dose steroids for adrenal/pituitary insufficiency) is not considered systemic treatment.
2. Concurrent Systemic Therapy: Use of systemic corticosteroids (≥10 mg/day of prednisone or equivalent) or other immunosuppressants (e.g., cyclosporine, cyclophosphamide, azathioprine, methotrexate, thalidomide) within 14 days before the first dose, or use of immunostimulants (e.g., interferon, interleukin-2) within 4 weeks before the first dose.
3. Live Vaccines: Receipt of a live or attenuated live vaccine within 30 days before the first dose or potentially during the study period.
4. Antibiotic Use: Administration of broad-spectrum antibiotics by any route within 30 days prior to the first dose.
5. Previous Anticancer Therapies: Any prior antitumor treatments (radiotherapy, chemotherapy, surgery \[excluding biopsy\], PD-1/CTLA-4 dual immunotherapy, regorafenib, or other tyrosine kinase inhibitors).
6. Unresectable Factors: Tumors deemed unresectable or participants with surgical contraindications, or who refuse surgery.
7. Immunodeficiency: HIV infection, any other acquired or congenital immunodeficiency disorder, or a history of organ or allogeneic bone marrow transplantation (excluding corneal transplantation).
8. Hepatitis B/C Co-infection:

   HBsAg-positive and/or HBcAb-positive with HBV DNA \>10\^4 copies/mL (≈2000 IU/mL).

   Anti-HCV antibody-positive with HCV-RNA \>10\^3 copies/mL. Patients positive for both HBsAg and HCV-RNA are excluded.
9. Other Malignancies: Any other malignancies within the past 5 years or concurrent malignancies, except for treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.
10. Uncontrolled Effusions: Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage.
11. Severe Pulmonary Conditions: Known active pulmonary tuberculosis, radiation pneumonitis, drug-induced pneumonitis, or other severe pulmonary diseases/impairments.
12. Renal Failure: Renal failure requiring hemodialysis or peritoneal dialysis.
13. Active Infection or Fever: Active infection, unexplained fever ≥38.5°C within 7 days prior to study treatment, or baseline WBC count \>15 × 10\^9/L.
14. Cardiac Conditions: Poorly controlled or clinically significant cardiac conditions, including:

    NYHA Class II or higher heart failure, LVEF \<50% Unstable angina Myocardial infarction within 1 year prior to randomization Clinically significant arrhythmias requiring treatment or intervention QTc \>450 ms (men), or QTc \>470 ms (women)
15. Hypertension: Poorly controlled (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) despite antihypertensive therapy, or a history of hypertensive crisis/encephalopathy.
16. Recent Thrombosis: Arterial or venous thrombosis within 6 months prior to enrollment (e.g., stroke, transient ischemic attack, cerebral hemorrhage, cerebral infarction, deep vein thrombosis, pulmonary embolism).
17. Coagulopathy: Known hereditary or acquired bleeding/thrombotic disorders (e.g., hemophilia, coagulopathy).
18. Significant Bleeding: Evidence or history of bleeding. Any Grade ≥3 hemorrhage within 4 weeks prior to study treatment (per CTCAE v5.0).
19. Vascular Invasion: Tumor invasion of major blood vessels or a high likelihood thereof during the study, potentially leading to life-threatening bleeding as judged by imaging.
20. Wounds or Ulcers: Severe, unhealed or dehiscent wounds, active ulcers, or untreated fractures.
21. Major Vascular Disease: Major vascular disorders within 6 months prior to study treatment (e.g., requiring surgical repair for an aneurysm or recent peripheral arterial thrombosis).
22. Major Surgery: Major surgery (other than diagnostic) within 4 weeks prior to study treatment, or planned major surgery during the study period (excluding the planned study-related procedure).
23. Abdominal Fistula, Perforation, or Abscess: Such events within 6 months prior to study treatment.
24. Long-Term NSAIDs or Anticoagulants: Need for long-term or high-dose NSAIDs (≥325 mg aspirin) or anticoagulant therapy.
25. Known Drug Allergy: Suspected or known allergy to any study drug or its components relevant to this trial.
26. Monoclonal Antibody Hypersensitivity: History of severe hypersensitivity reactions to any monoclonal antibody, or known hypersensitivity/allergy to QL1706, regorafenib, oxaliplatin, capecitabine, or any of their components.
27. Difficulty Swallowing: Inability or difficulty swallowing oral study drugs.
28. Pregnant or Breastfeeding: Women who are pregnant or lactating.
29. Other Factors: Any other factors that may affect study outcomes or lead to premature termination, including a history of alcohol or drug abuse, severe diseases (including psychiatric disorders) requiring combination treatment, significant laboratory abnormalities, or family/social circumstances that, in the investigator's judgment, compromise patient safety or study integrity.