Metabolic Reprogramming in Macrophage Fate and Immunity. 

Macrophages are versatile immune cells that exhibit remarkable plasticity and perform diverse functions across tissues. Beyond their well-established roles in host defense, inflammation, and tissue repair, macrophages serve as critical regulators of metabolic homeostasis. In response to environmental cues, macrophages adopt distinct activation states—ranging from classically activated (or M1), pro-inflammatory phenotypes induced by IFN-γ and TLR signaling, to alternatively activated (or M2), anti-inflammatory states driven by IL-4 and IL-13. These phenotypes are metabolically programmed to support their specialized functions, with M1 macrophages relying heavily on glycolysis and M2 macrophages engaging oxidative metabolism, particularly lysosomal lipolysis and mitochondrial fatty acid oxidation (FAO).

Our laboratory is dedicated to uncovering the metabolic and epigenetic mechanisms that regulate macrophage polarization, with a particular focus on macrophage-driven immunity in cancer and inflammatory diseases. Using integrated transcriptomic and metabolomic approaches, we have shown that glutaminolysis and N-linked glycosylation are essential for the development of immunosuppressive macrophages. Additionally, we identified mTORC2 as a central regulator that coordinates gene expression and metabolic rewiring in immunosuppressive (anti-inflammatory) macrophages during both tumorigenesis and helminth infection.

Our research has recently identified endoplasmic reticulum (ER) stress signaling as a critical driver of metabolic adaptation and pro-tumoral function in tumor-associated macrophages (TAMs). We discovered that TAMs experience sustained ER stress within the tumor microenvironment, leading to selective activation of the PERK branch of the unfolded protein response. This signaling cascade upregulates phosphoserine aminotransferase 1 (PSAT1), a key enzyme in the serine biosynthesis pathway. PSAT1-driven serine metabolism plays an essential role in maintaining mitochondrial fitness and supporting the oxidative metabolic program required for TAM-mediated immunosuppression. These findings define a novel tumor-induced PERK–PSAT1 signaling axis that links ER stress to serine biosynthesis and mitochondrial metabolism, thereby reinforcing the suppressive phenotype of TAMs and suppressing anti-tumor T cell responses.

Our ongoing research seeks to understand how mitochondrial homeostasis supports cellular fitness and directs the immunosuppressive program of TAMs. We are dissecting the molecular mechanisms that govern mitochondrial dynamics, metabolic resilience, and intracellular signaling in TAMs, and how these processes converge with immune pathways to support their immunosuppressive activity in tumors. By identifying and targeting key metabolic vulnerabilities - such as mitochondrial dysregulation and tumor-driven biosynthetic reprogramming - we aim to “recondition” TAMs to restore effective immune surveillance. Ultimately, we aim to advance the development of macrophage-targeted interventions that reprogram the immunosuppressive tumor microenvironment, enhance anti-tumor immunity, and overcome resistance to current immunotherapies.