Autophagy-mediated Secretion of Intracellular Antigens Co-opts Antibody Responses to Drive Neutrophil-Dependent Tumor Progression
How intracellular proteins, normally hidden from the immune system, become targets of tumor-associated antibody responses remains unresolved, as does the function of such autoantibodies encoded by tumor-infiltrating B cells (TIL-Bs). Using monoclonal antibodies (mAbs) cloned from TIL-Bs in a spontaneous hepatocellular carcinoma (HCC) model, we define a class of antigens: secreted intracellular antigens (SICAs). Tumors co-opt upregulated autophagy to release cytosolic proteins, exemplified by ALDH1L1, through HSP90-mediated autophagy-dependent unconventional secretion. The resulting autoantibodies form immune complexes at the tumor site, where the SICA is locally available, recruiting and reprogramming neutrophils into tumor-associated neutrophils that drive tumor progression. Both neutrophil depletion and loss of Fcγ receptor binding abolish this effect. Autophagy-mediated SICA secretion and the corresponding autoantibody response are conserved in HCC patients and extend to lung, breast and cervical cancers. Tumors thus reshape their secretome to hijack humoral immunity, highlighting the SICA-autoantibody-FcγR axis as a potential therapeutic target.
Authors
- Wenjing Su (ORCID: https://orcid.org/0000-0002-1775-9115)
- Pengli Zheng (ORCID: https://orcid.org/0000-0002-3797-4023)
- Yanan Wang (ORCID: https://orcid.org/0000-0002-8864-5609)
- Israel Tojal da Silva (ORCID: https://orcid.org/0000-0002-4687-1499)
- Dong Gao (ORCID: https://orcid.org/0000-0003-1821-2741)
- Anqi Xia (ORCID: https://orcid.org/0000-0001-9638-3074)
- Minxiang Xie (ORCID: https://orcid.org/0000-0003-0108-9556)
- Thiago Y. Oliveira (ORCID: https://orcid.org/0000-0002-2654-0879)
- Shibo Jiang (ORCID: https://orcid.org/0000-0001-8283-7135)
- Weiyu Jiang (ORCID: https://orcid.org/0000-0001-5732-9163)
- Xiaonuo Ma (ORCID: https://orcid.org/0009-0007-7455-4080)
- Qianqian Zhang (ORCID: https://orcid.org/0000-0003-2996-2310)
- Qiao Wang (ORCID: https://orcid.org/0000-0001-6416-1733)
- Yixiao Zhang (ORCID: https://orcid.org/0000-0003-1540-4334)
- Yanfeng Liu (ORCID: https://orcid.org/0000-0003-2633-4765)
- Juan He (ORCID: https://orcid.org/0000-0002-3064-219X)
- Yidan Gao (ORCID: https://orcid.org/0000-0001-9392-9377)
- Fan Cao (ORCID: https://orcid.org/0009-0009-8890-0567)
- Xuan Tao (ORCID: https://orcid.org/0009-0009-9513-2711)
- Yifei Qian (ORCID: https://orcid.org/0009-0000-6086-6509)
- Qianyu Li (ORCID: https://orcid.org/0009-0002-4001-4215)
- Yingying Guo (ORCID: https://orcid.org/0009-0004-2499-203X)
- Wei Wu (ORCID: https://orcid.org/0009-0005-2404-9479)
- Yiming Long (ORCID: https://orcid.org/0009-0002-9945-4717)
Institutions
- King University (US)
- Shanghai Medical College of Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Fudan University (CN)
- AC Camargo Hospital (BR)
- Shandong Tumor Hospital (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Zhejiang University (CN)
- Rockefeller University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-11-02
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-0463
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00