Objective:

To propose a mechanistic hypothesis explaining how cancer cells remodel their microenvironment through reactive oxygen species (ROS) signaling.

Approach:

• Mechanistic Hypothesis: The transformation of the tumor microenvironment (TME) is driven by a coordinated ROS signaling cascade initiated by cancer cells.
• Evidence Presentation: Three converging lines of evidence support the proposed mechanism, including a critical iron chelation experiment designed as the crucial mechanistic validation.

Key Findings:

• Cancer cells generate superoxide (O2•-) through NADPH oxidase (NOX) upregulation and mitochondrial respiration.
• Superoxide is converted to hydrogen peroxide (H2O2), which triggers lysosomal membrane permeabilization (LMP) in cancer-associated fibroblasts (CAFs).
• This process leads to a shift in CAF metabolism toward fatty acid oxidation (FAO), producing metabolites that fuel tumor growth and create an immunosuppressive microenvironment.

Interpretation:

The study suggests a redefinition of immunotherapy resistance as a metabolic infrastructure problem.

Limitations:

• The complete integrated mechanism remains to be validated experimentally.
• Individual steps of the proposed cascade are supported by existing literature but require further experimental confirmation.

Conclusion:

Targeting stromal metabolic engineering in combination with checkpoint blockade may help address resistance in cold tumors.