This study aims to determine the safety and maximum tolerated dose (MTD) of YMN-136 vaccine through a dose escalation trial, and to investigate whether YMN-136 vaccine can assist in the treatment of patients with metastatic colorectal cancer.

Inclusion Criteria:

1. Voluntarily sign the informed consent form, be able to understand and agree to follow the prescribed research procedures and visits;

2. Aged 18-75 years, both male and female are eligible;

3. Histologically confirmed unresectable advanced colorectal adenocarcinoma;

4. Patients with colorectal cancer liver metastasis who have failed third-line treatment, defined as those who have experienced disease progression (based on RECIST 1.1 criteria) or terminated treatment due to intolerance to toxicity after completing at least three different treatment regimens in the standard sequence during systemic treatment for colorectal cancer. The specific treatment pathway usually includes:

   • First-line treatment: Chemotherapy combined with targeted drugs (such as FOLFOX/FOLFIRI combined with anti-EGFR cetuximab or anti-VEGF bevacizumab).
   • Second-line treatment: Switch to a different chemotherapy regimen (e.g., FOLFIRI for second-line treatment if FOLFOX was used for first-line treatment) and replace the targeted drug (e.g., alternating between anti-EGFR and anti-VEGF drugs).
   • Third-line treatment: Standard third-line drugs include Regorafenib, TAS-102, or Furadixone, or novel drugs participating in clinical trials.

5. Eastern Cooperative Oncology Group (ECOG) physical status score: 0 or 1;

6. Expected survival ≥12 weeks;

7. During the screening period, the organ function levels must meet the following requirements:

   • Absolute neutrophil count (ANC) ≥1.5×10^9/L;
   • Platelet count (PLT) ≥100×10^9/L;
   • Hemoglobin (Hb) ≥90g/L;
   • Total bilirubin (TBIL) ≤1.5×ULN;
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN, and ≤5×ULN for patients with liver metastasis;
   • Serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance rate (Cockcroft-Gault formula) ≥45 mL/min;
   • International normalized ratio (INR), prothrombin time (PT) ≤1.5×ULN;
   • QTc interval calculated according to Fridericia criteria, ≤450ms for males and ≤470ms for females; • Urine routine test/24-hour urine protein quantitation: urine protein qualitative test ≤1+ (if urine protein qualitative test ≥2+, then 24-hour urine protein <1g is acceptable for enrollment);
   • Cardiac function: left ventricular ejection fraction ≥50%

8. Qualified patients (males or females) with reproductive capacity must agree to use a medically approved physical contraceptive method (such as intrauterine device, condom, tubal or vasectomy ligation, etc.) during the trial period and within 6 months after the last dose; female patients of childbearing age must have negative serum or urine HCG test results during the screening period.

Exclusion Criteria:

1. Patients with extensive peritoneal metastasis or intestinal obstruction; patients with uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
2. Patients known to be allergic to the components of the investigational drug (such as lipid nanoparticles, RNA vectors) or similar drugs;
3. Patients who have previously received vaccine therapy;
4. Patients who have received chemotherapy, targeted therapy, or immunotherapy within 4 weeks before the first dose;
5. During the dose escalation and dose expansion phases: Patients who have received anti-tumor treatment, such as chemotherapy, radiotherapy, targeted therapy, immunotherapy, biotherapy, or treatment with drugs from other clinical trials, within 4 weeks or 5 drug half-lives (whichever is shorter, but at least 14 days) before the first dose; Patients who have taken traditional Chinese medicine or traditional Chinese patent medicines and simple preparations with anti-tumor indications within 14 days before the first dose;
6. Patients who are expected to use immunosuppressive drugs during the study period within 4 weeks before the first dose, except for corticosteroid nasal sprays, inhalants, or systemic prednisone ≤10 mg/day and equivalent treatments;
7. Patients with a history of organ transplantation, bone marrow transplantation, or hematopoietic stem cell transplantation;
8. Patients who have received attenuated live vaccines within 28 days before the first dose;
9. During the dose escalation and dose expansion phases: Patients with symptomatic, untreated, or requiring continuous treatment (including corticosteroids and antiepileptic drugs) for central nervous system (CNS) metastasis (previously treated patients who have had stable clinical symptoms for at least 4 weeks before enrollment, have excluded evidence of new or expanding metastasis, and have discontinued steroid treatment may be enrolled; patients with asymptomatic brain metastasis and no need for treatment may be enrolled);
10. During the dose escalation and dose expansion phases: Patients who have not recovered to baseline or grade 0-1 (excluding alopecia and pigmentation) as defined by NCI CTCAE v5.0 after previous anti-tumor treatment. Patients with reasonably expected irreversible toxicity that will not be exacerbated by the study drug may be enrolled after confirmation with the investigator;
11. Patients with a history of autoimmune diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease, etc. Type 1 diabetes, hypothyroidism that can be controlled only by replacement therapy, and skin diseases that do not require systemic treatment (such as vitiligo and psoriasis) can be included in the trial;
12. history of immediate hypersensitivity reactions, eczema or asthma that cannot be controlled by topical corticosteroids;
13. history of other malignant tumors, except for curable tumors that have been cured, such as basal or squamous cell skin cancer, superficial bladder cancer or cervical carcinoma in situ, and breast carcinoma in situ.
14. Concurrent uncontrollable concomitant diseases, including but not limited to: unexplained fever > 38.5°C (subjects with tumor-related fever to be determined by the investigator for inclusion in the study), symptomatic congestive heart failure with New York Heart Association (NYHA) functional class ≥2, left ventricular ejection fraction (LVEF) <50%, poorly controlled hypertension (systolic blood pressure >160mmHg and/or diastolic blood pressure >100mmHg after treatment, and clinically significant as assessed by the investigator), unstable angina or acute myocardial infarction within 3 months prior to the first dose, poorly controlled arrhythmia; patients with chronic obstructive pulmonary disease, asthma, interstitial lung disease, and decreased lung function;
15. patients with active infection who currently require systemic anti-infective treatment; patients with active tuberculosis;
16. known human immunodeficiency virus (HIV)-positive individuals, individuals with active syphilis spirochete infection; individuals who are HBsAg and/or HBcAb positive and HBV-DNA >500 IU/L; individuals who are HCV-RNA positive;
17. patients with an expected survival of <3 months (based on clinical assessment or Child-Pugh C liver function).