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MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies

Bavani Subramaniam1, Wai Chin Chong1, Aylar Babaei1

  • 1Brain Tumor Institute, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC 20012, USA.

Cells
|December 24, 2025
PubMed

Insights

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in 15% of cancers, creating vulnerabilities. This review updates MTAP loss incidence, its metabolic impact, and therapeutic strategies, highlighting challenges and future directions for targeted cancer therapies.

Area of Science:

  • Oncology
  • Genetics
  • Biochemistry

Background:

  • Homozygous deletion of the 9p21.3 locus, including CDKN2A/B and methylthioadenosine phosphorylase (MTAP) genes, affects 15% of human cancers.
  • While CDKN2A is a known tumor suppressor, MTAP's role in tumorigenesis is context-dependent, impacting the methionine salvage pathway.
  • Loss of MTAP creates synthetic vulnerabilities, yet targeted therapies have shown limited clinical success.

Purpose of the Study:

  • To provide an updated perspective on MTAP loss incidence across various cancer types.
  • To elucidate the impact of MTAP loss on tumor metabolism, immune microenvironment, and progression.
  • To summarize preclinical and clinical therapeutic strategies targeting MTAP-null tumors.

Main Methods:

  • Systematic literature review and analysis of existing data on MTAP loss in cancer.
  • Evaluation of preclinical studies investigating therapeutic strategies for MTAP-deficient tumors.
  • Assessment of the current landscape of clinical trials for MTAP-targeted inhibitors.

Main Results:

  • Consolidated incidence data of MTAP loss in diverse cancers.
  • Elucidation of MTAP loss effects on tumor metabolism and immune interactions.
  • Summary of preclinical findings and clinical trial outcomes for MTAP-targeted therapies.

Conclusions:

  • MTAP loss presents a significant therapeutic target with complex downstream effects.
  • Current MTAP-targeted therapies face limitations, necessitating improved strategies.
  • Future research should explore rational combination therapies, potentially beyond the PRMT5/MAT2A axis, to effectively treat MTAP-null cancers.
Keywords:
CDKN2Acancermetabolismmethylthioadenosine phosphorylasetherapy

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