Cancer cachexia as an immunometabolic syndrome: targeting the immunometabolic interface with traditional Chinese Medicine monomers and formulas

Abstract

Cancer cachexia is conventionally viewed as muscle wasting but is increasingly recognized as a tumor-driven immunometabolic syndrome. This systemic disorder is characterized by a vicious cycle of metabolic dysregulation, systemic inflammation, and immune evasion, severely compromising the efficacy of immune checkpoint inhibitors (ICIs). Conventional single-target therapies have largely failed to disrupt this redundant pathological network. Here, we comprehensively review the therapeutic potential of Traditional Chinese Medicine (TCM) as multi-target network modulators acting at the immunometabolic interface. At the micro-level, TCM-derived monomers (such as curcumin, andrographolide, and epigallocatechin gallate (EGCG)) bidirectionally target this interface by concurrently suppressing muscle catabolism (via ubiquitin-proteasome and ferroptosis pathways) and reprogramming the immunosuppressive tumor immune microenvironment (TIME) (downregulating PD-L1 and inhibiting MDSCs/Tregs). At the macro-level, chromatographically characterized multi-herb formulas offer systemic recalibration via the gut-muscle-immune axis, utilizing microbial metabolites to restore intestinal barrier integrity, curb systemic inflammation, and epigenetically reinvigorate exhausted CD8+ T cells. Clinically, integrating TCM with ICIs presents a promising synergistic strategy to restore patient eligibility, optimize immunotherapeutic responses, and mitigate treatment-related adverse events. This review provides a mechanistic framework for positioning TCM as a potential systemic adjuvant to break the cachexia-immunosuppression loop in modern oncology.