Immune checkpoint blockade (ICB) therapy has transformed cancer treatment, but many tumors remain resistant. A new study from 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—while also revealing a potential strategy to overcome this resistance.
The 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 vital to advancing cancer care,” said Binfeng Lu, member of the CDI, member of the Georgetown University’s Lombardi Comprehensive Cancer Center, and professor of Medical Sciences at the Hackensack Meridian School of Medicine. “Our findings show that while some mutations render tumors resistant to treatment, they also reveal a specific vulnerability.”
While p53 mutations are the most common genetic alterations in human cancer, their role in cancer immunotherapy has been complex and, at times, contradictory. The CDI team discovered that certain p53 mutations in colorectal-cancer models actually hinder the efficacy of immunotherapy by manipulating cellular metabolism.
The researchers utilized CRISPR-Cas9 to delete mutant Trp53 in preclinical models of colorectal cancer. They observed that when the mutant Trp53 was removed, the tumors became significantly more susceptible to anti-PD-1 immunotherapy.
The mechanism centers on autophagy, a cellular recycling process that supports tumor survival under stress. Under normal conditions, p53 regulates cell growth in part by restraining mTORC1 signaling. The team discovered that certain mutant forms of p53 exhibit a selective retention-of-function, preserving their ability to suppress mTORC1 despite losing canonical functions such as p21 induction. This sustained inhibition of mTORC1 leads to increased autophagy, which enables tumor cells to better withstand immune-mediated stress, including cytotoxic signals from T cells. In this way, mutant p53 actively maintains a protective metabolic state that limits the effectiveness of anti-tumor immunity.
When the researchers removed the mutant Trp53, mTORC1 activity was restored and autophagy was reduced, effectively stripping away a key survival mechanism in the tumor cells. As a result, the cancer cells became much more vulnerable to attack by the immune system.
“Mutant p53 loses its core tumor-suppressive functions but selectively retains mTORC1 suppression, driving autophagy and enabling tumors to evade immune attack and resist immunotherapy,”conclude the authors.
“We believe that by targeting the crosstalk between p53 and the mTORC1 pathway, we may be able to sensitize tumors to immunotherapy and improve outcomes for patients,” Lu added.
The study was a collaborative effort involving researchers from the Hackensack Meridian School of Medicine, the University of Pittsburgh School of Medicine, and the Georgetown’s Lombardi Comprehensive Cancer Center.