Cancer cachexia: molecular basis and therapeutic advances

Abstract The dynamic interplay between neoplastic cells and the host has been increasingly recognized as important players in the pathogenesis of cancer cachexia, a syndrome affecting ~50–80% of cancer patients with various incidences of different types of malignancies. Despite its prevalence, a comprehensive understanding of cancer cachexia progression, with a holistic view at the cross-organismal, cellular and molecular levels, remains elusive. In this review, we undertake an in-depth exploration of the relevant target organs and their regulatory roles in cancer cachexia, with a particular focus on macroenvironmental interactions via various organismal crosstalk axes. Moreover, we highlight how systemic metabolic remodeling, a hallmark of cancer cachexia, plays essential roles in modulating the inflammatory responses of immune and stromal cells in the tumor microenvironment (TME). These cellular responses, in turn, disrupt energy metabolism in distant organs and perturb organismal homeostasis by secreting a variety of mediators that activate specific signaling pathways, thereby fostering a vicious cycle that exacerbates cancer cachexia. We comprehensively summarize these complex cellular and molecular networks that constitute reciprocally regulatory dynamics between systemic metabolic reprogramming and inflammatory cascades. Notably, targeting the multifaceted interplay of organismal metabolic remodeling and cancer-associated inflammation holds great promise for clinical translation, as illustrated by a series of innovative therapeutic strategies and ongoing clinical trials aimed at mitigating cachexia in cancer patients.