This is a randomized, parallel, open-label, multicenter exploratory clinical study designed to investigate the efficacy and safety of iparomlimab and tuvonralimab in combination with fruquintinib plus heterogeneous radiotherapy, compared with fruquintinib monotherapy, as the third-line and subsequent-line treatment for patients with oligometastatic colorectal cancer.

Inclusion Criteria:

• Patients aged 18 to 75 years (inclusive).
• Histologically or cytologically confirmed stage Ⅳ primary colorectal cancer.
• No more than 5 oligometastatic lesions, with metastases usually limited to one or a few specific organs (e.g., liver, lung, etc.), and the metastatic lesions are deemed suitable for stereotactic body radiation therapy (SBRT) by the investigator.
• Failure of at least 2 prior lines of standard therapy (based on fluorouracil, oxaliplatin, irinotecan, bevacizumab, cetuximab).

Note: Adjuvant/neoadjuvant therapy is permitted. If recurrence occurs during adjuvant/neoadjuvant therapy or within 6 months after its completion, the adjuvant/neoadjuvant therapy will be regarded as the first-line therapy for advanced disease.

• At least one extracranial measurable lesion meeting the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

• Prior radiotherapy is permitted, but it must be more than 4 weeks before study enrollment. In addition, the lesions selected for radiotherapy and evaluable lesions in this study must be untreated with radiotherapy, and the prior radiotherapy must not affect the normal tissue dose of radiotherapy in this study. (Note: If radiotherapy was received before enrollment, detailed radiotherapy-related parameter data must be provided.)

• If a subject has undergone surgery, he/she must have fully recovered from the toxicities and complications of the surgical intervention before the start of treatment, and enrollment will be considered only after the wound is completely healed.

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

• Expected survival of ≥12 weeks.

• Adequate function of major organs (no use of any blood components or cell growth factors within 2 weeks before enrollment), meeting the following requirements:

  1. Bone marrow function: Absolute neutrophil count (ANC) ≥1.5×10⁹/L, white blood cell (WBC) count ≥4.0×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin (Hb) ≥90 g/L.
  2. Hepatic function: Serum total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN). If serum total bilirubin level >1.5×ULN, direct bilirubin level must be ≤ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (up to 5×ULN for patients with liver metastases).
  3. Renal function: Blood urea nitrogen (BUN) and serum creatinine (Cr) ≤1.5×ULN (with creatinine clearance rate (CCr) ≥50 mL/min).
  4. Cardiac function: Normal cardiac function with left ventricular ejection fraction (LVEF) ≥50%.
  5. Coagulation function: International normalized ratio (INR) ≤1.5×ULN, activated partial thromboplastin time (APTT) ≤1.5×ULN.

• Male or female patients of childbearing potential must voluntarily use effective contraceptive methods during the study and within 6 months after the last study drug administration, such as double barrier contraception, condoms, oral or injectable contraceptives, intrauterine devices, etc. All female patients will be considered of childbearing potential unless they have natural menopause, artificial menopause, or sterilization (e.g., hysterectomy, bilateral adnexectomy, ovarian irradiation, etc.).

Exclusion Criteria:

• Prior treatment with anti-PD-1/PD-L1, anti-CTLA-4 agents, or other investigational immunotherapeutic agents.

• Severe autoimmune diseases, including active inflammatory bowel disease (Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis), etc.

• Symptomatic interstitial lung disease or active infectious/non-infectious pneumonitis.

• Risk factors for intestinal perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer, or other known risk factors for intestinal perforation.

• History of other malignancies; however, patients with cured localized tumors such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, cervix, or breast may be enrolled.

• Patients planning to undergo or having previously received organ or allogeneic bone marrow transplantation.

• Clinically significant moderate to severe ascites requiring therapeutic paracentesis or drainage, or Child-Pugh score >2 (except for radiologically detected minimal ascites without clinical symptoms); uncontrolled moderate or large pleural effusion or pericardial effusion.

• History of gastrointestinal bleeding or definite bleeding tendency within 6 months prior to initiation of study treatment, including: high-risk or severe esophagogastric varices, active local peptic ulcer lesions, persistent positive fecal occult blood test. (Patients with positive baseline fecal occult blood may be retested; if still positive, esophagogastroduodenoscopy (EGD) is required. Patients with EGD evidence of bleeding-risk varices are excluded.)

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment.

• Known congenital or acquired bleeding disorders (e.g., coagulopathy) or thrombotic tendency such as hemophilia; currently using or having recently used (within 10 days before study treatment) full-dose oral or injectable anticoagulants or thrombolytic agents for therapeutic purposes. (Prophylactic use of low-dose aspirin or low-molecular-weight heparin is permitted.)

• Currently using or having recently used (within 10 days before study treatment) aspirin (> 325 mg/day, maximal antiplatelet dose), dipyridamole, ticlopidine, clopidogrel (≥75 mg), or cilostazol.

• Thrombotic or embolic events within 6 months prior to initiation of study treatment, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), pulmonary embolism, etc.

• Active infection, heart failure, myocardial infarction within 6 months, unstable angina, or uncontrolled arrhythmia.

• Any physical or clinical laboratory abnormality that, in the investigator's opinion, may interfere with study outcomes or increase the risk of treatment complications, or other uncontrolled medical conditions.

• Patients requiring urgent palliative radiotherapy or emergency surgery (spinal cord compression, cerebral herniation, pathological fracture) as judged by the investigator.

• Breastfeeding or pregnant female patients.

• Congenital or acquired immunodeficiency disorders including human immunodeficiency virus (HIV) infection, or history of organ transplantation or allogeneic stem cell transplantation.

• Patients with psychiatric disorders, substance abuse, or social issues affecting compliance, as determined by the treating physician.

• Active infection including active tuberculosis is excluded. Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection may be enrolled if disease is stable following antiviral therapy.

• Administration of live attenuated vaccines within 30 days prior to enrollment. (Note: Injectable seasonal influenza vaccines are mostly inactivated and permitted; intranasal formulations are usually live attenuated and prohibited.)

• Poorly controlled cardiac symptoms or diseases including:

  1. New York Heart Association (NYHA) Class ≥II cardiac insufficiency or LVEF <50% on echocardiography;
  2. Unstable angina;
  3. Myocardial infarction within 1 year prior to initiation of study treatment;
  4. Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention;
  5. QTc interval >450 ms (males) or >470 ms (females) calculated by Fridericia formula. (If QTc is abnormal, three consecutive measurements at 2-minute intervals may be performed and averaged.)

• Hypertension not adequately controlled by antihypertensive therapy (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, based on average of ≥2 measurements). History of hypertensive crisis or hypertensive encephalopathy.

• Major vascular disease within 6 months prior to initiation of study treatment (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis).

• Severe, non-healing or dehiscent wound, active ulcer, or untreated fracture.

• Major surgery (except diagnostic procedures) within 4 weeks prior to initiation of study treatment, or expected major surgery during the study period.

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

• History of intestinal obstruction or clinical signs/symptoms of gastrointestinal obstruction within 6 months prior to initiation of study treatment, including partial obstruction related to underlying disease requiring parenteral hydration, parenteral nutrition, or tube feeding.

• Patients presenting with partial obstruction, obstruction syndrome, or signs/symptoms of ileus at initial diagnosis may be enrolled if they received definitive (surgical) treatment resulting in resolution of symptoms.

• Evidence of intra-abdominal free air not explained by recent paracentesis or surgery.

• Metastatic disease involving major airways or vessels (e.g., complete occlusion of main portal vein or vena cava due to tumor invasion is excluded; main portal vein is defined as the confluence of splenic and superior mesenteric veins and its bifurcation into right and left intrahepatic branches) or large central mediastinal mass (<30 mm from carina).

• History of hepatic encephalopathy.

• Current interstitial pneumonitis or interstitial lung disease; history of interstitial pneumonitis or lung disease requiring corticosteroid treatment; pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), pneumoconiosis, drug-related pneumonitis, idiopathic pneumonia, or evidence of active pneumonitis on screening chest CT with severely impaired pulmonary function. (History of radiation pneumonitis in radiation field is permitted.) Active tuberculosis.

• Active autoimmune disease or history of autoimmune disease with potential recurrence (including but not limited to autoimmune hepatitis, interstitial lung disease, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism). Patients with controlled hypothyroidism requiring only hormone replacement may be enrolled. Patients with skin diseases not requiring systemic therapy (vitiligo, psoriasis, alopecia), controlled type 1 diabetes mellitus on insulin, or childhood asthma in complete remission without adult intervention may be enrolled. Asthma requiring medical intervention with bronchodilators is excluded.

• Use of immunosuppressive agents or systemic corticosteroids (>10 mg/day prednisone or equivalent) for immunosuppressive purposes within 14 days prior to initiation of study treatment.

• Known severe hypersensitivity to any monoclonal antibody or anti-angiogenic targeted therapy.

• Seere infection within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for infection, bacteremia, or severe pneumonia; therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment. (Patients receiving prophylactic antibiotics are eligible.)

• Patients with any other conditions that, in the investigator's judgment, may affect study outcomes or lead to premature discontinuation, such as alcoholism, drug abuse, other severe comorbidities (including psychiatric disorders), significant laboratory abnormalities, or family/social issues compromising patient safety, will be excluded.