This is a Phase II clinical study aimed at evaluating the safety, tolerability, antitumor efficacy, PK and immunogenicity of AK146D1 combined with AK112 in advanced breast cancer.

Inclusion Criteria:

1. Be able to understand and voluntarily sign the written informed consent form.
2. Aged of ≥ 18 years and ≤75 years.
3. ECOG PS 0 or 1.
4. The expected lifespan is ≥3 months.
5. Patients with histologically confirmed locally advanced, recurrent, or metastatic breast cancer who are not eligible for curative surgical resection; and who have histologically or cytologically confirmed HER2-negative disease.
6. At least one measurable lesion according to RECIST v1.1. Patients with only bone lesions or cutaneous lesions are not ineligible for enrollment.
7. Have sufficient organ function.
8. Females patients must not be pregnant at screening or have evidence of non-childbearing potential. Agree to use medically accepted methods of contraception.

Exclusion Criteria:

1. Patients had breast cancer amenable to curative treatment at study enrollment.
2. Concurrent other histopathological types confirmed by tumor histology or cytology.
3. Having other active malignancies within 3 years.
4. Currently participating in another interventional clinical study.
5. Presence of active metastases to the central nervous system. For patients with asymptomatic brain metastasis or stable symptoms after treatment can be included.
6. Prior treatment with any therapy targeting Trop-2 or Nectin-4, or any chemotherapy agent targeting topoisomerase I.
7. Receipt of systemic anti-tumor therapy (including chemotherapy, immunotherapy, biological agents, etc.) within 4 weeks prior to the first dose.
8. Toxicity of previous antineoplastic therapy has not resolved to NCI CTCAE 6.0 grade 1 or lower.
9. Patients with clinically significant cardiovascular or cerebrovascular diseases or risks.
10. Patients with active autoimmune diseases requiring systemic treatment within 2 years.
11. Receipt of systemic anti-infective therapy within 2 weeks prior to the first dose.
12. Known to be positive for HIV and other infections.
13. Previous history of severe hypersensitivity reactions.
14. Live attenuated vaccines were received within 4 weeks.
15. Patients with a history of mental illness and incapacitated or limited capacity.
16. Any disease or condition that, in the opinion of the investigator, would compromise patient safety or interfere with study assessments.