Metabolic Disorders Rewire Systemic and Tumor Immunity to Shape Anti-Tumor Responses in Cancer Patients

Lisa Huang (Advisors: Liuqing Yang, PhD and Chunru Lin, PhD)

The global rise in metabolic diseases, including obesity and metabolic dysfunction-associated steatohepatitis (MASH), poses a major challenge for cancer immunotherapy. Patients with these conditions have higher cancer incidence, develop more aggressive tumors, and respond poorly to immune checkpoint blockade. However, the molecular and cellular mechanisms linking metabolic stress to immune dysfunction remain incompletely understood.

Here, we investigated how metabolic disease reshapes immune fate through three interconnected axes: amino acid metabolism, stress adaptation, and noncoding RNA regulation. In MASH, dysregulated phenylalanine (Phe) metabolism emerged as a key contributor to B-cell dysfunction. Under elevated Phe, B cells showed stage-specific vulnerabilities: activated B cells survived but exhibited an imbalance between germinal center and extrafollicular differentiation, whereas plasma cells were prone to apoptosis. These defects were associated with impaired p-eIF2α–mediated integrated stress responses. To therapeutically correct this impairment, we developed a noncoding RNA lipid nanoparticle (LNP) that enhances PAH-mediated Phe metabolism. Combined with anti–PD-1 therapy, this approach restored B-cell function, promoted differentiation, and improved tumor control and immune activation in NASH models. In parallel, we identified the small nucleolar RNA SNORD46, upregulated in obesity, as a repressor of IL-15 transcription via reduced STAT5 recruitment, impairing NK and T-cell activation. Blocking SNORD46 or restoring IL-15 signaling enhanced CAR-NK cell efficacy, revealing a strategy to overcome obesity-associated immune dysfunction.

Collectively, our findings highlight metabolic stress as a multilayered regulator of immune fate and uncover opportunities to restore immune competence and enhance immunotherapy in metabolically compromised cancers.

Advisory Committee:

• Liuqing Yang, PhD, Chair
• Chunru Lin, PhD, Co-Chair
• Michael Curran, Phd
• Jianjun Gao, PhD
• Leng Han, PhD
• Ahmed Kaseb, PhD
• Wantong Yao, MD, PhD

Join via Zoom (Please contact Ms. Huang for her Zoom meeting info.)