Kasra Mardani
1 
, Yaser Abolhasani
2 , Ahmadreza Maghsoudi
3 , Reza Farzaneh
4 , Zahed Karimi
5 , Maryam Marahemi
6 , Mohamadnavid Vanda
7 , Anna Ghorbani Doshantapeh
8 , Naeem Nikpour
9* 1 Department of Infectious Diseases, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Operating Room Technology, School of Paramedical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
3 Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Nursing, Faculty of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran
5 Department of Internal Medicine, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
6 Department of Infectious Diseases, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
7 Department of General Surgery, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
8 Department of Hematology-Medical Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
9 Department of Hematology and Medical Oncology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
Abstract
Cancer cachexia defined by progressive loss of skeletal muscle with or without fat depletion, affects many cancer patients and significantly impairs quality of life, treatment tolerance, and survival. Recent findings have elucidated the central role of the inflammatory-metabolic axis as a bidirectional crosstalk between systemic inflammation and profound metabolic derangements in cancer cachexia pathogenesis. Several studies detected that, tumor-derived factors and host immune responses trigger chronic elevation of pro-inflammatory cytokines, which activate key signaling pathways that disrupt metabolic homeostasis. This inflammatory milieu induces hypermetabolism, insulin resistance, and aberrant substrate utilization, while simultaneously stimulating muscle proteolysis by ubiquitin-proteasome and autophagy-lysosome systems and promoting adipose tissue lipolysis through browning of white fat. Recent concepts highlight the contribution of tumor exosomes carrying microRNAs and proteins that reprogram host metabolism, organ crosstalk involving liver acute-phase response and gut microbiome alterations, and the role of specific immune cell populations in sustaining inflammation. Meanwhile, metabolic dysfunction itself can amplify inflammation, creating a self-perpetuating cycle that accelerates wasting. These insights challenge the historical view of cachexia as merely a consequence of reduced food intake, positioning it as an active, tumor-driven process. Current therapeutic strategies targeting single cytokines have shown limited efficacy, emphasizing on the need for multimodal approaches that concurrently modulate inflammatory drivers and restore metabolic balance. Therefore, the dynamic interplay within this axis offers promising modalities for early detection biomarkers and mechanism-based interventions to mitigate this devastating syndrome.