Author ORCID Identifier

https://orcid.org/0000-0002-1859-3073

Date of Graduation

5-2026

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Liuqing Yang Ph.D.

Committee Member

Chunru Lin MD. Ph.D.

Committee Member

Jianjun Gao MD, Ph.D.

Committee Member

Ahmed Kaseb MD

Committee Member

Michael Curran Ph.D.

Committee Member

Leng Han Ph.D.

Committee Member

Wantong Yao MD, Ph.D.

Abstract

The global rise in metabolic diseases such as obesity and metabolic dysfunction-associated steatohepatitis (MASH) has created a major challenge for cancer immunotherapy. Individuals with these conditions face higher cancer incidence and respond poorly to immune checkpoint inhibitors and cellular therapies. Rather than acting solely on tumors, metabolic dysfunction dismantles antitumor immunity both locally and distally. Distally, chronic systemic inflammation and stromal remodeling distort the architectural integrity of secondary lymphoid organs. This systemic decay disrupts germinal center organization and impairs the priming of effector cells, effectively collapsing coordinated humoral and cellular immunity before it even reaches the tumor. Locally, metabolic dysfunction re-engineers the tumor microenvironment across three distinct axes. First, sustained nutrient excess and lipid accumulation alter tumor signaling, driving aggressive growth and the expression of immune-evasive ligands. Second, a hostile cytokine milieu and mitochondrial dysfunction force infiltrating T cells and B cells into states of terminal exhaustion and metabolic paralysis. Third, pathological fibrosis and stromal remodeling create physical and chemical barriers that disrupt tertiary lymphoid structures and shield the tumor from immune infiltration. Despite growing clinical recognition of these phenomena, the precise molecular crosstalk driving this multi-layered resistance remains incompletely understood, representing a critical barrier to optimizing immunotherapy outcomes for this growing patient population. To dissect the molecular mechanisms underlying this systemic immune failure, this dissertation investigates two interconnected axes through which distinct metabolic stressors reprogram immune cell fate.

The first centers on how obesity-driven noncoding RNA dysregulation suppresses NK cell fitness and renders cellular immunotherapy ineffective. To identify circulating mediators of obesity-associated immune suppression, snoRNA expression was profiled in human serum across a range of BMI values, revealing that SNORD46—a C/D box small nucleolar RNA—is elevated in obese donors and inversely associates with NK cell tumor infiltration across cancer types. Saturated fatty acids drive C/EBPβ phosphorylation at T235, promoting SNORD46 transcription and secretion from adipocytes. Once in circulation, SNORD46 physically binds IL-15 via its G11 nucleotide, acting as a natural IL-15 antagonist that disrupts ligand-receptor engagement, blocks IL-15-dependent autophagy in NK cells, and impairs their viability and cytotoxic capacity. Simultaneously, SNORD46 suppresses an unconventional IL-15 signaling cascade in adipocytes—mediated through FER kinase-dependent phosphorylation of CD36 and MGLL—that normally promotes lipolysis and adipose browning, linking the same snoRNA axis to both metabolic and immune dysfunction. These phenotypes were recapitulated in Snord46G11A/G11A knockin mice, in which a single nucleotide mutation dramatically enhances SNORD46-IL-15 binding affinity and drives spontaneous obesity. Critically, CAR-NK cell therapy that was effective under lean conditions lost efficacy against colorectal and triple-negative breast cancer xenografts under diet-induced obesity, and treatment with SNORD46 power inhibitors restored NK cell viability, rescued tumor infiltration, and significantly improved tumor control—establishing snoRNA-targeting as a strategy to reverse obesity-associated cellular immunotherapy resistance.

The second axis examines how amino acid dysregulation in MASH corrupts the organizational integrity of tertiary lymphoid structures and undermines checkpoint immunotherapy response. TLS predicts immunotherapy response across cancer types, yet the metabolic determinants of TLS maturation remain unknown. Integrating multiplex imaging, spatial transcriptomics, spatial metabolomics, and single-cell profiling across human and mouse MASH-driven hepatocellular carcinoma, TLS were found to be structurally present but functionally immature, characterized by selective loss of plasma cell programs. Co-registered metabolomic imaging identified phenylalanine as the sole amino acid specifically enriched within immature TLS cores, establishing a spatial link between amino acid dysregulation and defective humoral immune organization. Mechanistically, excess phenylalanine activates GCN2-dependent stress sensing while chronic type I interferon signaling simultaneously suppresses PERK-eIF2α activity, producing an ISR-uncoupled state that sustains BACH2/BTLA-mediated differentiation restraint in B cells. This two-checkpoint model explains how MASH-associated metabolic stress first blocks germinal center B cell progression into plasma cells, then drives apoptosis of mature plasma cells whose biosynthetic demands exceed the cell's stress-buffering capacity skewing follicular B cells toward extrafollicular or apoptotic fates and leaving TLS structurally intact but immunologically inert. Correcting phenylalanine excess through dietary restriction, the PAH cofactor BH4, or liver-targeted lipid nanoparticles delivering HULC—a long noncoding RNA that enhances PAH enzymatic activity—restored TLS maturation and rescued anti-PD-1 efficacy in vivo.

Together, these findings establish a unifying framework in which metabolic disease dismantles antitumor immunity through distinct but complementary mechanisms: noncoding RNA-mediated cytokine antagonism that impairs innate immune fitness, and amino acid-driven ISR dysregulation that arrests adaptive B cell programs. Both axes converge on a failure of immune cells to complete the differentiation and effector transitions required for durable antitumor responses, and both are amenable to molecularly targeted correction. This work demonstrates that metabolic disease does not merely create an immunosuppressive tumor microenvironment. It systematically redefines immune homeostasis at the systemic, cellular, and organelle levels, and that restoring metabolic competence represents a principled strategy to improve the efficacy of modern immunotherapies in patients with obesity- and MASH-associated cancers.

Keywords

Metabolic Dysfunction-Associated Steatohepatitis (MASH), Hepatocellular Carcinoma (HCC), Tumor Microenvironment (TME), Tertiary Lymphoid Structures (TLS), Integrated Stress Response (ISR), Phenylalanine Metabolism, B Cell Differentiation, Anti-PD-1 Resistance, Spatial Omics (Spatial Metabolomics & Transcriptomics), Phenylketonuria (PKU), Obesity, NK Cells

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