Related Experiment Video

Updated: Jul 19, 2025

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
08:19

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

6.0K

Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity

Andrew A Guirguis1,2,3, Yaara Ofir-Rosenfeld4, Kathy Knezevic1

  • 1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Cancer Discovery
|August 7, 2023
PubMed

Insights

Inhibiting METTL3 triggers an interferon response, enhancing T-cell killing of cancer cells. Combining METTL3 inhibitors with anti-PD-1 therapy shows superior preclinical activity by targeting distinct cancer clones.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Enhancing antitumor immunity is crucial for cancer treatment.
  • Novel strategies are needed to increase cancer cell immunogenicity.
  • METTL3 is an RNA methyltransferase involved in various cellular processes.

Purpose of the Study:

  • To investigate the effects of METTL3 inhibition on antitumor immunity.
  • To explore the potential of METTL3 inhibitors as cancer therapeutics.
  • To evaluate the combination of METTL3 inhibition with anti-PD-1 therapy.

Main Methods:

  • Utilized a novel enzymatic inhibitor of METTL3.
  • Employed unbiased CRISPR screens to identify key mediators.
  • Conducted experiments in immunocompetent mouse models.
  • Applied SPLINTR barcoding to analyze clonal responses.

Main Results:

  • METTL3 inhibition globally decreased N6-methyladenosine (m6A) levels, leading to double-stranded RNA (dsRNA) formation.
  • dsRNA sensing and interferon signaling were identified as key mediators of enhanced T-cell killing.
  • METTL3 inhibition demonstrated efficacy comparable to anti-PD-1 therapy alone.
  • Combination therapy exhibited significantly greater preclinical activity than single agents.
  • Distinct malignant clones were targeted by METTL3 inhibition and anti-PD-1 therapy, with combination therapy overcoming resistance.

Conclusions:

  • METTL3 inhibition induces a cell-intrinsic interferon response via dsRNA formation, a novel immunomodulatory mechanism.
  • This mechanism is distinct from current immunotherapies, supporting combination with agents like anti-PD-1.
  • The findings provide a strong molecular and preclinical rationale for using METTL3 inhibitors in combination with immune-checkpoint blockade to augment antitumor immunity in clinical settings.

More Related Videos

In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice00:07

In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice

Published on: August 23, 2019

7.4K
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice07:36

Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice

Published on: June 12, 2021

6.6K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
557
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
6.7K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.7K