Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but many tumors remain resistant. A new study by researchers at the Hackensack Meridian Center for Discovery and Innovation (CDI) identifies a previously unrecognized mechanism by which mutations in the p53 gene can limit the effectiveness of immunotherapy, as well as potential strategies to overcome this resistance.
The findings, published in the journal Cell Death and Disaster, could help make future cancer treatments more effective.
This study focuses on the p53 tumor suppressor gene, widely known as the “guardian of the genome.”
Understanding the nuances of how p53 mutations affect tumor behavior is essential to advancing cancer treatment. Our findings show that while some mutations make tumors resistant to treatment, they also reveal specific vulnerabilities. ”
Binfeng Lu, member of CDI, Georgetown University Lombardi Comprehensive Cancer Center, and professor of medical sciences at Hackensack Meridian School of Medicine
Although p53 mutations are the most common genetic alterations in human cancer, their role in cancer immunotherapy is complex and sometimes contradictory. The CDI team discovered that certain p53 mutations in colorectal cancer models actually impede the effectiveness of immunotherapy by manipulating cellular metabolism.
Researchers utilized CRISPR-Cas9 to delete mutant Trp53 in a preclinical model of colorectal cancer. They observed that when mutant Trp53 was removed, tumors became significantly more sensitive to anti-PD-1 immunotherapy.
This mechanism focuses on autophagy, a cell recycling process that supports tumor survival under stress. Under normal conditions, p53 controls cell proliferation in part by suppressing mTORC1 signaling. The researchers found that certain mutant forms of p53 exhibit selective retention of function, retaining the ability to suppress mTORC1 despite losing standard functions such as p21 induction. This sustained inhibition of mTORC1 increases autophagy, making tumor cells more resistant to immune-mediated stress such as cytotoxic signals from T cells. In this way, mutant p53 actively maintains a protective metabolic state that limits the effectiveness of antitumor immunity.
When the researchers removed mutant Trp53, mTORC1 activity was restored and autophagy was reduced, effectively stripping tumor cells of an important survival mechanism. As a result, cancer cells have become much more vulnerable to attack by the immune system.
“Mutant p53 loses its core tumor suppressor function but selectively retains mTORC1 suppression, driving autophagy and allowing tumors to evade immune attack and resist immunotherapy,” the authors conclude.
“We believe that targeting the crosstalk between p53 and mTORC1 pathways has the potential to increase tumor sensitivity to immunotherapy and improve patient outcomes,” Lu added.
The study was a collaboration involving researchers from Hackensack Meridian School of Medicine, the University of Pittsburgh School of Medicine, and Georgetown’s Lombardi Comprehensive Cancer Center.
sauce:
Hackensack Meridian Health
Reference magazines:
Rabbani Motlag, A. Others. (2026). Suppression of mTORC1 by Trp53 mutations increases resistance to immune checkpoint inhibition. cell death and disease. DOI: 10.1038/s41419-026-09067-4. https://www.nature.com/articles/s41419-026-09067-4
