Cancer therapy and cachexia

Abstract

A central challenge in cancer therapy is the effective delivery of anticancer treatments while minimizing adverse effects on patient health. The potential dual impact of therapy is clearly illustrated in cancer-associated cachexia, a multifactorial syndrome characterized by involuntary weight loss, systemic inflammation, metabolic dysregulation, and behavioral alterations such as anorexia and apathy. While cachexia research often focuses on tumor-driven mechanisms, the literature indicates that cancer therapies themselves, particularly chemotherapies and targeted treatments, can initiate or exacerbate the biological pathways driving this syndrome. Here, we explore how therapeutic interventions intersect with the pathophysiology of cachexia, focusing on key organ systems including muscle, adipose tissue, liver, heart, and brain. We highlight examples such as therapy-induced upregulation of IL-6 and growth-differentiation factor 15, both contributing to reduced nutrient intake and a negative energy balance via brain-specific mechanisms. At the level of nutrient release and organ atrophy, chemotherapies also converge with cancer progression, for example, activating NF-κB in muscle and PKA/CREB signaling in adipose tissue. By examining how treatment timing and modality align with the natural trajectory of cancer cachexia, we underscore the importance of incorporating physiological endpoints alongside tumor-centric metrics in clinical trials. Such integrative approaches may better capture therapeutic efficacy while preserving patient well-being.

Figure 1. Conceptual framework: systemic interplay between cancer, therapy, and organ dysfunction in cachexia.

Tumor-secreted factors lead to changes in the cellular compartments which ultimately, cause biochemical changes that may create a positive feedback loop to drive factor secretion. Cancer therapies affect cachexia development by interacting with tumors, for example, by influencing tumor-secreted factors and altering cellular and biochemical components. More specifically, the figure illustrates the interconnected systemic interactions among cancer, its treatments (surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapies), and their effects on organ function, indicating the central role of interorgan communication in patient morbidity and the development of cancer cachexia. Each organ-specific list represents a set of examples of clinically observed symptoms (e.g., breathlessness in the lungs) and underlying biochemical or pathological changes (e.g., disrupted redox balance in the liver or cytokine-driven immune dysregulation).

Figure 2. Detrimental contribution of treatment toxicity to cachexia.

The interplay between inflammatory pathways, hormone signaling, end-organ damage, and patient experience (frequently reported by patients or relatives) in the intersection of progression of cancer cachexia and therapy is illustrated. Example treatments or treatment categories as well as toxicity examples are provided within each domain, demonstrating how they may contribute to systemic dysfunction and cachexia development.

Figure 3. Mechanistic pathways underlying tumor- and therapy-induced cachexia across key organs.

Examples of converging molecular pathways through which tumors and cancer therapies drive cachexia-associated changes in five major organ systems: muscle, liver, fat, brain, and heart. Arrows indicate the connected mechanistic pathway resulting in physiological dysfunction in each organ, ultimately leading to a convergent effect. For example, in the brain, elevated GDF-15 or IL-6 levels, resulting from tumor progression or chemotherapy, are detected by neurons in the area postrema, resulting in the activation of circuitry that leads to food avoidance and behavior changes driven by hormone signaling (42, 43, 94, 96). In the heart, tumor- and therapy-driven activation of TGF-β signaling promotes cardiac fibrosis and heart failure (–184). In the liver, tumor- and therapy-induced ROS accelerate fibrosis and impair liver function (47, 109, 139, 185, 186). In muscle, tumors and chemotherapy agents (e.g., doxorubicin, cisplatin) activate the NF-κB axis (inflammatory pathways), leading to atrophy via upregulation of MuRF1 and atrogin-1 (–192). In adipose tissue, lipolytic enzymes (HSL, ATGL) and β3-adrenergic/PKA/CREB signaling promote lipid mobilization and thermogenesis, leading to energy wasting and fat loss (–37, 39, 40). These molecular pathways collectively unmask or exacerbate cachexia and contribute to multi-organ dysfunction and failure during cancer progression and therapy. The figure illustrates only selected examples and does not represent a comprehensive set of molecular pathways or causalities. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; MMP2, matrix metallopeptidase 2; COL1A1, collagen type I alpha 1; COL3A1, collagen type III alpha 1; CGI-58, comparative gene identification-58; FFA, free fatty acid; PKA, protein kinase A; CREB, cAMP response element-binding protein; C/EBPβ, CCAAT/enhancer binding protein beta; UCP1, uncoupling protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PRDM16, PR domain containing 16; CPT1, carnitine palmitoyltransferase I; PDK4, pyruvate dehydrogenase kinase 4.

Figure 4. Dynamic effects of cancer treatment on outcome and cachexia.

Conceptualization of the interplay between cancer treatment efficacy and toxicity (therapeutic window), disease progression, and the risk of developing cachexia. (A) Concept: Cancer and treatment have reciprocal interactions via factors x₁, x₂…x_n and y₁, y₂…y_n, and both affect the host system over time. The composite interactions determine how much the global body function declines. 0 indicates a nonsymptomatic precancerous state when body function is well preserved, and 1 indicates the end point when body function declines to a survival threshold. (B) Specific example: Cisplatin treatment can reduce tumor burden and consequently tumor-associated GDF-15 levels, but it can also elevate GDF-15 levels through induction of cell stress in multiple tissues and can reduce its own excretion by reducing renal filtration rates. A net increase in GDF-15 level, therefore, can increase cachexia susceptibility potentially even in the context of reduced tumor burden. (C) A pseudotime representation of body function shows that as body function declines, the therapeutic benefits diminish, and the same intervention may ultimately become detrimental because of the host effect. Therefore, an early intervention when body function is still preserved may maximize net benefits and promote survival. As discussed in “Scope and considerations,”we did not include covariables in this discussion but acknowledge that they may have an impact on body function and the interaction between cancer and treatments.