Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting that impairs quality of life, limits responses to anticancer therapies, and increases mortality. Although excessive protein degradation has traditionally been viewed as a primary driver of muscle loss, cachectic muscle undergoes broader disruptions in proteostasis involving protein turnover, organelle quality control, stress adaptation, metabolism, and regenerative capacity. Accumulating evidence suggests that diverse tumor- and host-derived signals converge on interconnected transcriptional networks that coordinate these processes. Rather than functioning independently, transcription factors integrate inflammatory, metabolic, hormonal, and cellular-stress signals to orchestrate catabolic, stress-responsive, anabolic, and regenerative programs, with effects that vary with disease stage and cellular context. Importantly, these transcriptional responses are not uniformly pathological but can represent causal, adaptive, or compensatory programs. Epigenetic, post-transcriptional, and post-translational mechanisms add further regulatory layers that shape the activation and magnitude of these transcriptional programs. Emerging single-cell and multi-omic approaches have further revealed myofiber- and cell-specific regulatory networks that contribute to the heterogeneous response of skeletal muscle to tumor growth. In this review, we propose that transcriptional reprogramming represents a central integrative mechanism through which diverse catabolic signals remodel skeletal muscle proteostasis, and we examine how network-level regulation contributes to muscle adaptation and wasting in cancer cachexia. Defining which regulatory programs are causal, maladaptive, adaptive, or compensatory may reveal more precise biomarkers and therapeutic targets for preserving skeletal muscle mass and function in patients with cancer cachexia.
