This study is an open-label, multi-center phase II clinical trial aimed to evaluat the safety and preliminary efficacy of JS212 combination therapy in patients with advanced esophageal squamous cell carcinoma (ESCC).

Inclusion Criteria:

1. Male or female subjects aged 18 to 75 years (inclusive) at the time of signing the Informed Consent Form (ICF).
2. Histologically or cytologically confirmed esophageal squamous cell carcinoma (ESCC) that is locally advanced, recurrent, or metastatic, and not amenable to radical treatment.
3. No prior systemic anti-tumor therapy. For patients who received neoadjuvant/adjuvant therapy or radical concurrent chemoradiotherapy, the interval from the last dose of chemotherapy to disease recurrence or progression must be > 6 months to be eligible for screening.
4. At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Expected survival ≥ 12 weeks

Exclusion Criteria:

1. Prior treatment with any of the following: anti-PD-1 or anti-PD-L1 antibody therapy; ADC therapy targeting EGFR and/or HER3, or ADC therapy with a topoisomerase I inhibitor as the toxic payload;
2. Subjects at high risk of bleeding or esophageal fistula, e.g., lesions with large ulcers or direct invasion of vital adjacent organs such as the aorta or trachea;
3. Subjects with a history of gastrointestinal perforation and/or fistula within 6 months prior to the first dose;
4. Presence of active central nervous system (CNS) metastases;
5. Active autoimmune disease requiring systemic therapy (e.g., corticosteroids or immunosuppressive agents) within 2 years prior to the first dose;
6. Toxicities from prior anti-tumor therapy have not recovered to ≤ Grade 1 per CTCAE v6.0 or to the level specified in the inclusion/exclusion criteria;
7. Severe cardiovascular or cerebrovascular disease;
8. Known hypersensitivity or severe allergic reaction to the study treatment drugs, any of their components, or their excipients；