Targeted Degradation of sGRP78 Alleviates the Immunosuppressive Tumor Microenvironment

Abstract There is an urgent need for appropriate methods to identify patients who are sensitive to neoadjuvant therapy (NAT) for precise stratified treatment. Based on clinical proteomics screening and further validation in patient cohorts, we reported that soluble glucose‐regulatory protein 78 (sGRP78) could be a serological biomarker to infer the poor chemotherapy response in breast cancer. Consequently, an “sGRP78 index” 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‐10+/PD‐L1+ B subsets and Tregs infiltration, accompanied by accelerated tumor progression and metastasis. The following experiment revealed that sGRP78 bound with tumor‐infiltrating B cells, converting the latter into IL‐10+/PD‐L1+ ones, thereby promoting Treg formation and suppressing T cell‐mediated antitumor cytotoxicity. By fusing the GRP78‐selective 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’ sensitivity to NAT, as well as the potential of sGRP78 as a novel immune checkpoint target for cancer therapy.