Muscleblind proteins revealed to have a new role as anti-tumor agents

Over the past decade, cancer treatment has undergone a major transformation, from traditional, broadly acting therapies like cytotoxic chemotherapy and radiation to more precise and targeted approaches. Among these, immunotherapy has emerged as a powerful tool that leverages the body’s immune system to attack tumors. For example, CAR-T cell therapy, in which immune cells are engineered to directly target cancer, or immune checkpoint inhibitors, which prevent cancer from evading immune detection, have shown remarkable promise.

Despite these successes, response to immunotherapy remains inconsistent. While some patients experience dramatic responses, others see little or no benefit. One reason for this disparity is the incidence of "cold" tumors, or tumors that are less recognizable by the immune system. Researchers are now racing to discover how to turn cold tumors "hot" to improve treatment outcomes.

In a new study, Austin Gabel, an MD-PhD candidate, and Drs. Edie Crosse and James Thomas, postdoctoral fellows in the lab of Dr. Robert Bradley, a professor at Fred Hutchinson Cancer Center, identified an unexpected player in tumor immune recognition: the Muscleblind-like (MBNL) proteins. Wait—Muscleblind? These RNA-binding proteins were originally discovered in the fruit fly Drosophila melanogaster. Mutations in these genes led to abnormal development of fly muscles, as if the muscles were “blind” to developmental cues. Eye development was also affected—hence the name Muscleblind!

“Muscleblind-like (MBNL) proteins are a well characterized family of RNA binding proteins with a wide variety of previously described functions. They are well known for their critical role in the pathogenesis of myotonic muscular dystrophy – a disease causing very debilitating, progressive muscle weakness,” Gabel explained. 

“We find for the first time that MBNL proteins regulate the immune system in a variety of human cancers. We see that loss or reduced expression of MBNL proteins alters responses to interferon mediated signaling in both mice and humans correlates with reduced numbers of CD8+ T cells. This is particularly interesting as all cancers need to evade death by the immune system, and we think that MBNL proteins could serve as a novel target for future studies,” Gabel stated. These findings were recently published in PlosOne

Gabel’s investigation into MBNL proteins was sparked by a previous genome-scale CRISPR-Cas9 screen, which identified genes whose loss made melanoma cells more resistant to killing by cytotoxic T cells. Among the hits were MBNL1 and MBNL2. Gabel confirmed that knocking out MBNL1 and MBNL2 made cancer cells more resistant to T cell-mediated killing. This revealed a novel role for MBNL proteins in keeping cancer cells "visible" to immune cells. Without them, tumors could better evade immune surveillance.

To understand how MBNL proteins regulate this immune-evading phenotype, Gabel knocked out MBNL1 and MBNL2 in melanoma cells. These cells were then treated with interferon gamma, a key immune signaling molecule, followed by RNA sequencing to assess gene expression changes. The loss of MBNL proteins led to reduced expression of genes involved in MHC class I antigen presentation, a critical pathway that allows immune cells to recognize and attack cancer cells.

Without proper MHC class I expression, cancer cells become invisible to immune cells, allowing them to avoid immune destruction. Notably, this effect wasn’t limited to melanoma; similar reductions in MHC class I expression were observed in breast and colorectal cancer cells lacking MBNL proteins, suggesting a broad, tumor-agnostic role.

Gabel tested the hypothesis in vivo. Tumors lacking MBNL expression not only showed reduced surface MHC class I levels but also had significantly lower infiltration of immune cells, including CD8 T cells and natural killer cells, key players in anti-tumor immunity. These results reinforce the idea that MBNL proteins support immune recognition within the tumor microenvironment.

Finally, the team turned to human cancer datasets to determine whether MBNL’s role in immune regulation holds true in patients. Indeed, MBNL1 expression strongly correlated with T cell infiltration, particularly in melanoma, as well as in testicular and pancreatic cancers. Across a range of tumor types, MBNL1 ranked among the top genes associated with immune cell presence, rivaling known immune regulators.

“While our study establishes a link between MBNL expression, antigen presentation, and T cell-mediated tumor killing, the precise molecular mechanisms remain unclear,” the authors noted. “We hope this work inspires future studies investigating the link between MBNL and the immune system in both cancer and muscular dystrophy.” Gabel concluded. 

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Robert Bradley contributed to this research.

The spotlighted research was funded by ARCS Foundation, the Damon Runyon Foundation, the Leukemia & Lymphoma Society, Mark Foundation for Cancer Research, and Paul G. Allen Frontiers Group and The National Cancer Institute. 

Gabel AM, Crosse EI, Belleville AE, Hogg SJ, McKellar SA, Abdel-Wahab O, Thomas JD, Bradley RK. Muscleblind-like proteins are novel modulators of the tumor-immune microenvironment. PLoS One. 2025.