Tumor-intrinsic Warburg effect as the driver and therapeutic target for cancer-associated cachexia in mouse models

Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome affecting 50-80% of patients with advanced malignancies and still lacks FDA-approved interventions. It manifests as progressive loss of body weight, depletion of adipose and skeletal muscle tissues, metabolic inflexibility, and anemia, collectively worsening prognosis and compromising responses to systemic therapy. Accumulating evidence indicates that tumor-intrinsic metabolic reprogramming can sustain aggressive tumor growth and drive systemic energy imbalance, yet the specific molecular events linking oncogenic programs to host peripheral wasting remain incompletely defined. To dissect this tumor-intrinsic axis, we established subcutaneous tumor models in C57BL/6 mice using isogenic KP lung cancer cells (Kras G12D/+ ; p53 -/- ), KPL cells carrying additional Lkb1 loss (Kras G12D/+ ; p53 -/- ; Lkb1 -/- ), and B16F10 melanoma. KPL and B16F10 tumors induced a more severe cachectic phenotype than KP tumors, characterized by greater body weight decline, pronounced loss of adipose tissue and skeletal muscle, and more severe anemia. Thus, this KP/KPL isogenic tumor models provide us an opportunity to dissect the underlying mechanisms for CAC. First, we found that KPL tumors grew faster and relied more heavily on glycolytic metabolism than KP controls. Integrated proteomic and metabolomic profiling confirmed a shift toward aerobic glycolysis in KPL tumors, consistent with a strengthened Warburg effect. Follow-up experiments indicated that this metabolic shift was linked to LKB1 loss and heightened HIF activity. To test therapeutic relevance, we treated KPL- and B16F10-bearing mice with an FDA-approved HIF-2alpha inhibitor Belzutifan. Belzutifan reduced adipose and muscle loss, suggesting that dampening HIF signaling can lessen cancer-associated wasting, although anemia did not improve under this treatment, likely because systemic HIF-2alpha blockade reduces erythropoietin (EPO) production in these CAC mouse models. Collectively, our data identifies HIF-driven tumor-intrinsic Warburg effect as a central contributor to CAC in mouse models. Targeting HIF signaling can attenuate tumor-induced wasting and provides mechanistic proof-of-concept for metabolic reprogramming-directed CAC therapy although anemia issues remain. Moreover, our data indicated that rational combination regimens, such as co-administration of EPO, will be required to deliver full muscular, adipose, and hematologic rescue in CAC. These preclinical data warrant further investigation in patient-derived model systems, and eventually in clinical trials.