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Based on clinical proteomics screening and further validation in patient cohorts, we reported that soluble glucose\u2010regulatory protein 78 (sGRP78) could be a serological biomarker to infer the poor chemotherapy response in breast cancer. Consequently, an \u201csGRP78 index\u201d was established to accurately predict patient responses to NAT. When exploring the linked mechanisms on how sGRP78 confer the resistance, it was found that in high sGRP78 index tumors, there were more IL\u201010+\/PD\u2010L1+ B subsets and Tregs infiltration, accompanied by accelerated tumor progression and metastasis. The following experiment revealed that sGRP78 bound with tumor\u2010infiltrating B cells, converting the latter into IL\u201010+\/PD\u2010L1+ ones, thereby promoting Treg formation and suppressing T cell\u2010mediated antitumor cytotoxicity. By fusing the GRP78\u2010selective protease subtilase cytotoxin catalytic A subunit (subA) with a nanobody against HER2, we achieved the targeted degradation of sGRP78 within the breast cancer region, effectively reversing the immunosuppressive microenvironment. Our findings highlight the potential of sGRP78 index as a predictive signature to identify patients\u2019 sensitivity to NAT, as well as the potential of sGRP78 as a novel immune checkpoint target for cancer therapy.<\/jats:p>","DOI":"10.1002\/advs.202509921","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T03:51:47Z","timestamp":1757649107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeted Degradation of sGRP78 Alleviates the Immunosuppressive Tumor Microenvironment"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8468-1234","authenticated-orcid":false,"given":"Zhenghao","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and 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