Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Area of Science:

• Immunology
• Oncology
• Metabolic Reprogramming

Background:

• The host immune system influences tumor cell resistance to therapies like immunotherapy, chemotherapy, and radiotherapy.
• Understanding the mechanisms of immune-driven cross-resistance is crucial for effective cancer treatment.

Purpose of the Study:

• To investigate the molecular mechanisms by which the immune system induces cross-resistance to multiple cancer therapies.
• To identify potential therapeutic targets for overcoming immune-mediated treatment refractoriness.

Main Methods:

• Sequential in vitro and in vivo immune selection of murine and tumor cells using cytotoxic T lymphocytes.
• Analysis of molecular and metabolic changes, including epigenetic alterations, reactive oxygen species (ROS) accumulation, and HIF-1α stabilization.
• Assessment of tumor cell phenotype (stem-like, invasive) and response to antioxidant treatment.

Main Results:

• Immune selection leads to multimodality resistance via epigenetic loss of ATP synthase subunit ATP5H.
• ATP5H loss triggers ROS accumulation and HIF-1α stabilization, promoting a stem-like, invasive tumor phenotype.
• In vivo antioxidant administration reversed these changes and resensitized tumor cells to therapy.
• Reduced ATP5H expression in human tumors correlates with therapy failure, disease progression, and poor survival.

Conclusions:

• A core metabolic reprogramming pathway driven by immune selection underlies multimodality cancer therapy resistance.
• Targeting mitochondrial metabolic reprogramming, specifically ATP5H loss, offers a strategy to overcome immune-driven resistance.
• These findings have significant implications for clinical cancer management and improving therapeutic outcomes.