BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING

Abstract

High-grade serous ovarian cancer progresses within a lipid-rich ascites microenvironment that engages stress-adaptation programs supporting malignant growth, yet how failed stress resolution influences tumor progression remains incompletely defined. Here, we show that unresolved lysosomal stress restrains tumor progression by sustaining tumor cell-intrinsic STING activity and reorganizing antitumor immunity. We identify BLTP3A as a lysosomal stress-resolution factor in ovarian cancer and show that the common germline missense variant BLTP3A M1098T increases stress-induced lysosomal damage. Patients carrying M1098T had longer overall survival and tumors enriched for cytotoxic T cell-myeloid neighborhoods. In syngeneic tumors, Bltp3a loss or orthologous variant expression delayed progression and generated Cxcl9+ antigen-presenting macrophage niches; M1098T-expressing human tumors similarly promoted interferon-responsive myeloid and T-cell enrichment in humanized mice. Mechanistically, ascites-induced lysosomal stress activated a STING-ATF4-BLTP3A feedback program. BLTP3A dysfunction disrupted CASM-associated lysosomal stress resolution, resulting in prolonged STING activity and sustained tumor-derived IFN-{lambda} without increased cGAMP. Tumor-cell STING and IFN-{lambda} were required for immune remodeling and tumor control. Thus, BLTP3A-dependent lysosomal stress resolution constrains the persistence of stress-induced STING signaling, whereas failure of this response sustains a tumor-intrinsic inflammatory program that organizes protective antitumor immunity.

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BibTeX RIS

BibTeX

@misc{hosseini2026bltp3a,
  title = {{BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING}},
  author = {E. S. Hosseini and S. Wang and M. Arabzadeh and K. E. Warrington and M. T. Sogaard and A. Singh and W. Chen and L. Ranasinghe and R. Kumari and C. K. Alcott and A. Robinson and S. Yadav and W. Hu and J. Cao and E. Girda and E. P. White and C. S. Hinrichs and K. K. Payne},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.25.752224},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.25.752224v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING
AU  - E. S. Hosseini
AU  - S. Wang
AU  - M. Arabzadeh
AU  - K. E. Warrington
AU  - M. T. Sogaard
AU  - A. Singh
AU  - W. Chen
AU  - L. Ranasinghe
AU  - R. Kumari
AU  - C. K. Alcott
AU  - A. Robinson
AU  - S. Yadav
AU  - W. Hu
AU  - J. Cao
AU  - E. Girda
AU  - E. P. White
AU  - C. S. Hinrichs
AU  - K. K. Payne
PY  - 2026
DA  - 2026/09/25
PB  - bioRxiv
DO  - 10.64898/2026.09.25.752224
UR  - https://www.biorxiv.org/content/10.64898/2026.09.25.752224v1
AB  - High-grade serous ovarian cancer progresses within a lipid-rich ascites microenvironment that engages stress-adaptation programs supporting malignant growth, yet how failed stress resolution influences tumor progression remains incompletely defined. Here, we show that unresolved lysosomal stress restrains tumor progression by sustaining tumor cell-intrinsic STING activity and reorganizing antitumor immunity. We identify BLTP3A as a lysosomal stress-resolution factor in ovarian cancer and show that the common germline missense variant BLTP3A M1098T increases stress-induced lysosomal damage. Patients carrying M1098T had longer overall survival and tumors enriched for cytotoxic T cell-myeloid neighborhoods. In syngeneic tumors, Bltp3a loss or orthologous variant expression delayed progression and generated Cxcl9+ antigen-presenting macrophage niches; M1098T-expressing human tumors similarly promoted interferon-responsive myeloid and T-cell enrichment in humanized mice. Mechanistically, ascites-induced lysosomal stress activated a STING-ATF4-BLTP3A feedback program. BLTP3A dysfunction disrupted CASM-associated lysosomal stress resolution, resulting in prolonged STING activity and sustained tumor-derived IFN-{lambda} without increased cGAMP. Tumor-cell STING and IFN-{lambda} were required for immune remodeling and tumor control. Thus, BLTP3A-dependent lysosomal stress resolution constrains the persistence of stress-induced STING signaling, whereas failure of this response sustains a tumor-intrinsic inflammatory program that organizes protective antitumor immunity.
ER  -

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