Objective:

To synthesize current evidence on FTO's roles in cancer, particularly its impact on immune contexture, immune checkpoint regulation, metabolic reprogramming, and therapeutic resistance, based on preclinical studies.

Approach:

• Biological Functions of FTO: The review outlines FTO's role as an RNA demethylase and its context-dependent effects on tumor progression and immune evasion, influenced by tumor lineage and subcellular localization.
• Tumor Type-Specific Activity: It examines how FTO's activity varies across different tumor types, including its dual roles in promoting or restraining malignancy.
• Emerging Pharmacological Strategies: The review evaluates new FTO inhibitors and combination strategies with other therapies, highlighting the preclinical evidence supporting these approaches.

Key Findings:

• FTO functions as a context-dependent regulator in cancer, influencing tumor progression and immune evasion based on tumor lineage and competing m6A reader activities.
• The biological output of FTO is shaped by tumor lineage, subcellular localization, and competing m6A reader activities.
• FTO's roles in immune exclusion and modulation of PD-L1 expression are significant in the context of therapeutic resistance, as evidenced by preclinical studies.

Interpretation:

FTO's context-dependent roles complicate its classification as merely an oncogene or tumor suppressor, highlighting the need for a nuanced understanding of its functions in various cancers.

Limitations:

• Most evidence regarding FTO's roles in cancer is preclinical, lacking clinical validation and comprehensive understanding.
• Technical limitations of epitranscriptomic methods constrain inference and understanding of FTO's functions in various cancers.

Conclusion:

The review aims to bridge gaps in the literature regarding FTO's roles in cancer and suggests that context-aware targeting of FTO may enhance therapeutic strategies.