Immunotherapy may bring revolutionary changes to the preoperative neoadjuvant treatment mode for dMMR/MSI-H locally advanced rectal cancer. According to the existing theory, the use of Iparomlimab and Tuvonralimab may be the best solution. In this study, the investigators will perform single-cell sequencing of participants tissue samples, fully explore the multi-dimensional omics information of tumors and microenvironments, explore the characteristics of the treatment benefit population, and try to construct an efficacy prediction model to screen the treatment benefit population early and implement precise treatment.

Inclusion Criteria:

1. Patients willing to receive neoadjuvant therapy.

2. Age ≥18 years.

3. Histologically confirmed primary colorectal adenocarcinoma (without squamous or sarcomatoid components).

4. Radiologically assessed (contrast-enhanced CT or MRI) as surgically resectable stage IIB-III (limited to cT4 or cN+ per AJCC 8th edition).

5. Confirmed dMMR or MSI-H status by immunohistochemistry or MSI genetic testing.

6. Lesions diagnosed by investigators as amenable to radical resection (R0 resection) without requiring multi-organ resection prior to neoadjuvant therapy.

7. Voluntary participation with signed informed consent.

8. ECOG performance status score of 0-1.

9. No prior antitumor or immunotherapy before enrollment.

10. Adequate organ and bone marrow function defined as:

    1. Hematology: Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L; Platelets (PLT) ≥100×10⁹/L; Hemoglobin (HGB) ≥7.0 g/dL.
    2. Liver function: Total Bilirubin (TBIL) ≤1.5×ULN; Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) ≤3×ULN; Serum Albumin (ALB) ≥28 g/L.
    3. Renal function: Serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min; Urine dipstick shows protein <2+; for subjects with baseline urine dipstick protein ≥2+, a 24-hour urine collection must demonstrate protein <1 g.
    4. Coagulation: International Normalized Ratio (INR) ≤1.5 and Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN.

11. No severe comorbidities jeopardizing survival (life expectancy <5 years).

12. Fertile female subjects or male subjects with fertile partners must use effective contraception during and for 6 months after treatment. Postmenopausal status or negative urine/serum pregnancy test for premenopausal females.

Exclusion Criteria:

• 1.Prior antitumor therapy for the disease under investigation, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.

  2.Previous treatment with anti-PD-1, anti-PD-L1, anti-programmed death ligand 2 (PD-L2), or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents, or any other drugs targeting T-cell co-stimulation or immune checkpoint pathways (e.g., OX40, CD137), as well as adoptive cell immunotherapy.

  3.Concurrent participation in another interventional clinical study. 4.Treatment with any investigational drug or device within 4 weeks prior to the first dose of the study drug.

  5.Within 7 days before screening laboratory tests: receipt of blood transfusion, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), thrombopoietin (TPO), or IL-11 therapy.

  6.Use of immunosuppressive drugs within 4 weeks before the first dose of the study drug, excluding: intranasal/inhaled topical steroids or local steroid injections (e.g., intra-articular); systemic corticosteroids at doses ≤10 mg/day prednisone or equivalent; corticosteroids as premedication for allergic reactions (e.g., CT scan premedication).

  7.Use of Chinese herbal medicine with antitumor indications or immunomodulatory drugs (including thymosin, interferon, interleukin, etc.) within 1 week before the first dose of the study drug.

  8.Receipt of live or attenuated vaccines within 4 weeks before the first dose or anticipated during the study.

  9.Major surgery (e.g., craniotomy, thoracotomy, or laparotomy) within 4 weeks before the first dose, anticipated need for major surgery during the study (except protocol-defined radical resection for colon cancer), or presence of unhealed wounds, ulcers, or fractures.