Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl­transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole­cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.

Significance:

This work demonstrates that METTL3 inhibition stimulates a cell-intrinsic interferon response through dsRNA formation. This immunomodulatory mechanism is distinct from current immunotherapeutic agents and provides the molecular rationale for combination with anti–PD-1 immune-checkpoint blockade to augment antitumor immunity.

This article is featured in Selected Articles from This Issue, p. 2109

_{Received: January 03 2023
Revision Received: June 06 2023
Accepted: August 02 2023
Online ISSN: 2159-8290
Print ISSN: 2159-8274Funding}

Funding Group:

• Award Group:
  • Funder(s): Cancer Council Victoria
  • Principal Award Recipient(s): M.A. Dawson
• Award Group:
  • Funder(s): Sir Edward ‘Weary’ Dunlop Medical Research Foundation
  • Principal Award Recipient(s): M.A. Dawson
• Award Group:
  • Funder(s): National Health and Medical Research Council (NHMRC)
  • Award Id(s): Investigator Grant 1196749, Grants 1085015 | 1106444 | 1128984
  • Principal Award Recipient(s): M.A. Dawson
• Award Group:
  • Funder(s): mRNA Victoria Research Acceleration Fund
  • Principal Award Recipient(s): A.A.M.A. GuirguisDawson
• Award Group:
  • Funder(s): Howard Hughes Medical Institute (HHMI)
  • Award Id(s): Scholarship 55008729
  • Principal Award Recipient(s): M.A. Dawson
• Award Group:
  • Funder(s): Victorian Cancer Agency (VCA)
  • Award Id(s): MCRF
  • Principal Award Recipient(s): E.Y. Lam
• Award Group:
  • Funder(s): Leukemia and Lymphoma Society (LLS)
  • Award Id(s): Fellowship 3411-22
  • Principal Award Recipient(s): D. Vassiliadis

©2023 American Association for Cancer ResearchCancer Discov (2023) 13 (10): 2228–2247.

https://doi.org/10.1158/2159-8290.CD-23-0007 Article history

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