Lactic Acid Drives ESM1 to Attenuate DNA Damage and CD8+ T Cell Infiltration in Cancer

Area of Science:

• Cancer biology
• Tumor metabolism
• Immunology

Background:

• Lactate is a key byproduct of tumor metabolic reprogramming.
• Lactate influences DNA damage repair (DDR) and tumor immune infiltration.
• Understanding lactate's role in immune evasion is critical.

Purpose of the Study:

• To elucidate the molecular mechanisms of lactate-driven tumor DDR.
• To investigate how lactate promotes tumor immune evasion.
• To identify key molecular players in lactate-mediated immune suppression.

Main Methods:

• Treating cancer cells (HCC, LUAD, OC) with lactate, ESM1 shRNA/overexpression, or Akt1 inhibitor.
• Assessing proliferation, apoptosis, and DNA damage using EdU, flow cytometry, and comet assays.
• Evaluating protein expression via Western blot, PCR, immunofluorescence, and analyzing xenograft models and patient samples.

Main Results:

• Lactate upregulates ESM1 expression, reducing DNA damage in tumor cells.
• Lactate activates Akt1 signaling via ESM1, suppressing the cGAS pathway and inflammatory factors.
• ESM1 knockout enhances CD8+ T cell infiltration and tumor apoptosis, validated in patient samples.

Conclusions:

• Lactate, via ESM1 and Akt1, suppresses DDR and the cGAS-STING pathway.
• This suppression inhibits CD8+ T cell infiltration, promoting tumor immune evasion.
• Targeting the lactate-ESM1-Akt1 axis may overcome tumor immune suppression.