Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer

Sci Adv. 2026 Jan 16;12(3):eady5324. doi: 10.1126/sciadv.ady5324. Epub 2026 Jan 16.

Abstract

Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1+ cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys123 (K123) enhances its recognition of cis-acting elements, increases chromatin binding, and promotes androgen receptor splicing. Targeting lactate transport with monocarboxylate transporter inhibitors effectively restores ADT sensitivity. These findings reveal a metabolic-epigenetic axis linking lactate in the microenvironment to alternative splicing regulation and suggest a promising therapeutic strategy to overcome ADT resistance.

MeSH terms

  • Alternative Splicing*
  • Androgen Antagonists / pharmacology
  • Animals
  • Cancer-Associated Fibroblasts* / metabolism
  • Cancer-Associated Fibroblasts* / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lactic Acid* / metabolism
  • Male
  • Mice
  • Monocarboxylic Acid Transporters
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Tumor Microenvironment

Substances

  • Lactic Acid
  • Receptors, Androgen
  • AR protein, human
  • Androgen Antagonists
  • Monocarboxylic Acid Transporters