Lactate activates GPR81 to drive tumour-induced cachexia. Cancer cachexia affects 50–80% of cancer patients and accounts for 20% of cancer-related deaths, but the underlying mechanism remains unclear. This study shows that circulating lactate levels are positively correlated with body weight loss in cancer patients and in mouse models. Lactate infusion alone can trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Adipose-specific GPR81 ablation, like global GPR81 deficiency, ameliorates lactate- or tumour-induced adipose and muscle wasting in male mice, indicating that adipose GPR81 is the major mediator of lactate's catabolic effects. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the protein kinase A (PKA) pathway but is mediated by a cascade involving Gi–Gβγ–RhoA/ROCK1–p38. These findings highlight the therapeutic potential of targeting GPR81 for cancer cachexia. Cachexia is characterized by rapid weight loss and accounts for about 20% of cancer-related deaths. Patients with cancer cachexia experience asthenia, anorexia, anaemia and fatigue, leading to poor quality of life and poor tolerance to cancer therapies. While cancer cachexia is an outstanding unmet medical need, its underlying mechanism is poorly understood. Loss of fat and muscle mass are key features of cachexia. Inflammatory cytokines such as TNF, IL-6, TGF-β and IFN-γ have been implicated in stimulating adipose and muscle remodelling caused by cancer. However, anti-inflammatory treatments have not been effective in curing cancer cachexia. The study identifies lactate as a causal factor of cancer cachexia, with GPR81 as a key mediator of lactate signalling. Lactate activates thermogenic and lipolytic programmes in adipose tissue through the Gαi/o-Gβγ-RhoA/ROCK1-p38 cascade, independent of the classic adenylyl cyclase-cAMP-PKA pathway. Circulating lactate levels increase in cancer cachexia. In a mouse xenograft model of Lewis lung cancer (LLC), tumour-bearing mice exhibited weight loss and reduced white adipose tissue (WAT) and skeletal muscle mass. Untargeted metabolomics analysis showed that lactate levels were significantly increased in this model. In a more clinically relevant mouse model of spontaneous lung cancer, tumour-bearing mice experienced weight loss and elevated blood lactate levels. Serum lactate levels were closely correlated with body weight change in this model. In human patients with lung adenocarcinoma, serum lactate levels were elevated in those with cachexia and closely correlated with body weight loss. Surgical removal of lung tumoursLactate activates GPR81 to drive tumour-induced cachexia. Cancer cachexia affects 50–80% of cancer patients and accounts for 20% of cancer-related deaths, but the underlying mechanism remains unclear. This study shows that circulating lactate levels are positively correlated with body weight loss in cancer patients and in mouse models. Lactate infusion alone can trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Adipose-specific GPR81 ablation, like global GPR81 deficiency, ameliorates lactate- or tumour-induced adipose and muscle wasting in male mice, indicating that adipose GPR81 is the major mediator of lactate's catabolic effects. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the protein kinase A (PKA) pathway but is mediated by a cascade involving Gi–Gβγ–RhoA/ROCK1–p38. These findings highlight the therapeutic potential of targeting GPR81 for cancer cachexia. Cachexia is characterized by rapid weight loss and accounts for about 20% of cancer-related deaths. Patients with cancer cachexia experience asthenia, anorexia, anaemia and fatigue, leading to poor quality of life and poor tolerance to cancer therapies. While cancer cachexia is an outstanding unmet medical need, its underlying mechanism is poorly understood. Loss of fat and muscle mass are key features of cachexia. Inflammatory cytokines such as TNF, IL-6, TGF-β and IFN-γ have been implicated in stimulating adipose and muscle remodelling caused by cancer. However, anti-inflammatory treatments have not been effective in curing cancer cachexia. The study identifies lactate as a causal factor of cancer cachexia, with GPR81 as a key mediator of lactate signalling. Lactate activates thermogenic and lipolytic programmes in adipose tissue through the Gαi/o-Gβγ-RhoA/ROCK1-p38 cascade, independent of the classic adenylyl cyclase-cAMP-PKA pathway. Circulating lactate levels increase in cancer cachexia. In a mouse xenograft model of Lewis lung cancer (LLC), tumour-bearing mice exhibited weight loss and reduced white adipose tissue (WAT) and skeletal muscle mass. Untargeted metabolomics analysis showed that lactate levels were significantly increased in this model. In a more clinically relevant mouse model of spontaneous lung cancer, tumour-bearing mice experienced weight loss and elevated blood lactate levels. Serum lactate levels were closely correlated with body weight change in this model. In human patients with lung adenocarcinoma, serum lactate levels were elevated in those with cachexia and closely correlated with body weight loss. Surgical removal of lung tumours