Journal Club: MTAP deficiency confers resistance to cytosolic nucleic acid sensing and STING agonists

Science ; 9 Oct 2025; Vol 390, Issue 6769 DOI: 10.1126/science.adl4089

Structured Abstract

INTRODUCTION

Cytosolic nucleic acid–sensing pathways have emerged as promising therapeutic targets to enhance the efficacy of immune checkpoint blockade, especially in immunologically “cold” tumors. Activation of these pathways stimulates type I interferon (IFN-I) signaling and the expression of interferon-stimulated genes (ISGs), promoting immune cell recruitment and potentially converting cold tumors into immune-active, “hot” tumors. Stimulator of interferon genes (STING) agonists, which activate this innate immune pathway, have shown potent antitumor activity in preclinical models. However, clinical trials have not replicated these effects in patients, highlighting a translational gap and the need to better understand the regulatory mechanisms and resistance factors influencing STING pathway activation in human cancers.

RATIONALE

Chromosome 9p21.3, which is frequently homozygously deleted in multiple cancer types, includes the methylthioadenosine phosphorylase (MTAP) gene and nearby loci such as cyclin dependent kinase inhibitor 2A (CDKN2A), CDKN2B, and, in some cases, IFN-I gene clusters. Although co-deletion of the IFN cluster has been linked to the immune-cold phenotype associated with 9p21.3 loss, our findings show that MTAP deletion independently impairs cytosolic nucleic acid sensing. Analysis of The Cancer Genome Atlas (TCGA), excluding cases with homozygous IFN cluster deletions, revealed a positive correlation between MTAP and IFN-I expression. We also identified MTAP loss as a common feature in human tumors that is largely absent in standard mouse models. Collectively, these observations led us to hypothesize that MTAP deficiency intrinsically suppresses nucleic acid sensing and contributes to STING agonist resistance.

RESULTS

Using multiple isogenic cell line models, we found that MTAP deletion suppresses IFNβ and downstream ISG induction by down-regulation of interferon regulatory factor 3 (IRF3), a key transcription factor in nucleic acid sensing. Mechanistically, MTAP loss results in the accumulation of its substrate, methylthioadenosine (MTA), which inhibits the methyltransferase protein arginine methyltransferase 5 (PRMT5). In MTAP-intact cells, PRMT5 inhibition or knockdown similarly reduced IRF3 expression and impaired nucleic acid sensing, establishing PRMT5 as a positive IRF3 regulator. MTA is also secreted and can suppress PRMT5 activity and IRF3 in neighboring MTAP-proficient cells, contributing to a paracrine-immunosuppressive environment. We further identified the E3 ubiquitin ligase Midline-1 (MID1), which targets IRF3 for degradation, as being up-regulated in MTAP-deficient, PRMT5-inhibited, or PRMT5-depleted cells. PRMT5 represses MID1 by depositing the repressive histone mark symmetric dimethylation at arginine 3 of histone H4 (H4R3me2s) at its promoter; MTAP deficiency abrogates this regulation, leading to increased MID1 and IRF3 destabilization. Treatment with the US Food and Drug Administration–approved ornithine decarboxylase inhibitor DL-α-difluoromethylornithine (DFMO) reduced MTA, restored PRMT5 activity, suppressed MID1, and rescued IRF3 levels and nucleic acid sensing in MTAP-deficient cells. In syngeneic mouse tumor models, MTAP-deficient tumors were resistant to STING agonists. However, combination therapy with STING agonists and DFMO overcame this resistance, leading to robust antitumor responses and increased immune infiltration.

CONCLUSION

This study identifies MTAP deficiency as a key suppressor of cytosolic nucleic acid sensing and as a determinant of STING agonist resistance in human tumors. MTAP status may thus serve as a biomarker for patient stratification, and targeting polyamine metabolism may improve the clinical efficacy of STING-based immunotherapies. Mechanism-informed combination strategies may help to bridge the translational gap in innate immune activation therapies.