De novo lipogenesis controls antigen presentation and metastatic immune escape in triple-negative breast cancer.
- 1Weill Cornell Medicine of Cornell University
Abstract
Metastatic dissemination is a major cause of mortality in triple-negative breast cancer (TNBC), yet how tumor metabolic state regulates immune surveillance during metastasis remains poorly understood. Here, we identify de novo lipogenesis as a tumor-intrinsic determinant of immune visibility and metastatic progression. Genetic or pharmacologic disruption of fatty acid synthase (FASN) suppresses metastasis with limited effects on primary tumor growth and enhances tumor-cell major histocompatibility complex class I (MHC-I) antigen presentation and CD8+ T cell activation. Mechanistically, FASN-dependent lipogenesis sustains epidermal growth factor receptor (EGFR) palmitoylation, selectively maintaining PI3K-AKT-mTOR signaling without altering EGFR abundance, cell-surface localization, or MAPK activation. Disruption of FASN-dependent lipogenesis, EGFR palmitoylation, or mTOR signaling restores peptide-MHC-I presentation and enhances antigen-specific CD8+ T cell recognition and cytotoxicity. FASN loss increases the abundance of multiple antigen-processing machinery proteins without corresponding changes in MHC-I transcript abundance, supporting transcription-independent regulation of antigen presentation downstream of PI3K-AKT-mTOR signaling. Tumor-cell B2M depletion substantially restores metastatic outgrowth and circulating tumor cells following FASN loss, identifying MHC-I antigen presentation as a major mediator of lipogenesis-dependent metastatic immune escape. In patient-derived TNBC organoids and independent human breast cancer cohorts, elevated lipogenic gene expression correlated with PI3K-AKT-mTOR-related transcriptional programs and reduced immune-surveillance programs, without significant differences in MHC-I transcriptional signatures. Together, these findings define a tumor-intrinsic immunometabolic circuit in which de novo lipogenesis sustains EGFR palmitoylation and PI3K-AKT-mTOR signaling to regulate antigen presentation, thereby modulating tumor-cell immune visibility during metastatic progression.
Related
- Terms and conditions apply: A cytokine cocktail licenses astrocyte antigen presentation
- Early-onset spontaneous murine mammary tumors show increased lymphocyte representation and reduced MHC antigen presentation
- Orbital metastasis revealing occult metastatic prostate adenocarcinoma in a South African man: A rare initial ophthalmic presentation
- 1076 Patient-derived organoids reveal tumor-restricted noncanonical HLA-I antigen candidates in low mutation burden metastatic melanoma
- High-Resolution Spatial Transcriptomics Reveals Interferon-Associated Immune Niches and Antigen Presentation Programs in Inclusion Body Myositis
BibTeX
@misc{ko2026novo,
title = {{De novo lipogenesis controls antigen presentation and metastatic immune escape in triple-negative breast cancer.}},
author = {M. S. Ko and H. Withers and D. Ramchandani and J. McCormick and S. E. Carrasco and P. Amartey and A. Singh and L. Yoffe and G. E. Simmons and G. Zhang and W. H. Shen and V. Mittal},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.21.726063},
url = {https://www.biorxiv.org/content/10.64898/2026.05.21.726063v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - De novo lipogenesis controls antigen presentation and metastatic immune escape in triple-negative breast cancer.
AU - M. S. Ko
AU - H. Withers
AU - D. Ramchandani
AU - J. McCormick
AU - S. E. Carrasco
AU - P. Amartey
AU - A. Singh
AU - L. Yoffe
AU - G. E. Simmons
AU - G. Zhang
AU - W. H. Shen
AU - V. Mittal
PY - 2026
DA - 2026/05/21
PB - bioRxiv
DO - 10.64898/2026.05.21.726063
UR - https://www.biorxiv.org/content/10.64898/2026.05.21.726063v2
AB - Metastatic dissemination is a major cause of mortality in triple-negative breast cancer (TNBC), yet how tumor metabolic state regulates immune surveillance during metastasis remains poorly understood. Here, we identify de novo lipogenesis as a tumor-intrinsic determinant of immune visibility and metastatic progression. Genetic or pharmacologic disruption of fatty acid synthase (FASN) suppresses metastasis with limited effects on primary tumor growth and enhances tumor-cell major histocompatibility complex class I (MHC-I) antigen presentation and CD8+ T cell activation. Mechanistically, FASN-dependent lipogenesis sustains epidermal growth factor receptor (EGFR) palmitoylation, selectively maintaining PI3K-AKT-mTOR signaling without altering EGFR abundance, cell-surface localization, or MAPK activation. Disruption of FASN-dependent lipogenesis, EGFR palmitoylation, or mTOR signaling restores peptide-MHC-I presentation and enhances antigen-specific CD8+ T cell recognition and cytotoxicity. FASN loss increases the abundance of multiple antigen-processing machinery proteins without corresponding changes in MHC-I transcript abundance, supporting transcription-independent regulation of antigen presentation downstream of PI3K-AKT-mTOR signaling. Tumor-cell B2M depletion substantially restores metastatic outgrowth and circulating tumor cells following FASN loss, identifying MHC-I antigen presentation as a major mediator of lipogenesis-dependent metastatic immune escape. In patient-derived TNBC organoids and independent human breast cancer cohorts, elevated lipogenic gene expression correlated with PI3K-AKT-mTOR-related transcriptional programs and reduced immune-surveillance programs, without significant differences in MHC-I transcriptional signatures. Together, these findings define a tumor-intrinsic immunometabolic circuit in which de novo lipogenesis sustains EGFR palmitoylation and PI3K-AKT-mTOR signaling to regulate antigen presentation, thereby modulating tumor-cell immune visibility during metastatic progression.
ER -