Immune Cells Rewire Themselves to Keep Battling Tumors in Nutrient Poor Environments

Children's Hospital of Philadelphia researchers hope study findings will open a potential path to improve immunotherapy

PHILADELPHIA, April 29, 2026 /PRNewswire/ -- Children's Hospital of Philadelphia Pathology and Laboratory Medicine researchers uncovered how killer T cells – called CD8+ T cells – keep fighting inside tumors, where nutrients are scarce and conditions are harsh. The team found that rather than simply powering down, T cells rely on a natural stress-adaptation pathway to stay functional in these environments, and that this pathway is required for them to control cancer. The findings were reported today in the journal Immunity.

Tumors often create a hostile environment that starves immune cells of key fuels like glucose and certain amino acids. When T cells first enter these environments, they can lose strength and stop producing important proteins they need to fight cancer. Rather than focusing only on what goes wrong, the CHOP team took a different approach: investigating the natural properties that allow T cells to withstand stress in the first place.

In the study, Will Bailis, PhD, the study's lead author, and an assistant professor of Pathology and Laboratory Medicine at CHOP, and his team, looked at how activated CD8+ T cells respond when placed in tumor-like conditions – either in fluid taken from tumors or in lab media missing key nutrients like glucose, glutamine, or branched-chain amino acids. At first the T cells were weakened, but within a few hours they reorganized internally and recovered their function, even though the surrounding environment stayed nutrient poor. The team followed the cells' metabolic changes, tracked which genes were switched on and saw which messenger RNAs were used to make proteins. They also used drug treatments and genetic knockouts to identify the stress-sensing pathways that allow the cells to bounce back.

Central to this recovery is the integrated stress response (ISR), a cellular alarm system that turns on when conditions get tough. ISR activation raises levels of two key transcription factors, ATF4 and CEBPG, which work together to switch on a small but essential set of genes that help T cells take in and make their own amino acids and keep their mitochondria – the batteries of the cells – working. This coordinated program ensures a T cell can sustain its immune function even with less energy to work with.

When the team blocked the ISR pathway or removed the proteins ATF4 or CEBPG, the T cells couldn't bounce back properly. In preclinical models, they became exhausted faster and were less effective at fighting tumors. This shows that the ISR and those two factors help T cells stay resilient and active in nutrient-poor tumor environments. Because many solid tumors create similar stressful conditions, boosting this natural resilience could help patients with different types of cancer. Instead of trying to fix each stressor inside tumors one by one, this strategy strengthens T cells so they can cope with whatever stresses they meet.

"Our research points to a new angle for improving immunotherapy," said Bailis, who is also an assistant professor at the University of Pennsylvania. "Most treatments try to reinvigorate T cells once they're already worn down, but the stressful environment inside tumors pushes back against those therapies. Our work highlights what lets T cells stay resilient in the first place. If we can strengthen that built-in resilience, like how an athlete training at high altitude builds the capacity to perform under tough conditions, we may be able to help immunotherapies work for a much broader range of patients."

This work was supported by NIH grant R35GM138085 (WB), Paul Allen Institute Distinguished Investigator Award (WB), Ludwig Institute for Cancer Research (WB), NIH grant P30CA016520 (CSC), NIH grant R35GM154896 (CSC), Department of Defense grant HT9425- 23-1-0082 (CSC), NIH grant F31CA261156 (LT), and NIH T32CA009140 (KR)

Scaglione et al. "Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress." Immunity. Online April 29, 2026. DOI: 10.1016/j.immuni.2026.04.004.

About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

Contact: Jennifer Lee
Children's Hospital of Philadelphia
(267) 426-6084
[email protected]

SOURCE Children's Hospital of Philadelphia