Hidden Receptor Crosstalk Governs Lymphatic Failure After Cancer Therapy.

Cancer therapy imposes sustained mechanical and biochemical stress on lymphatic tissues, reshaping the signaling environments in which endothelial and contractile programs operate via molecular signals, cell-cell interactions, and mechanical forces. We propose that cancer-associated lymphedema arises from destabilized receptor crosstalk within integrated lymphatic signaling units rather than solely from anatomical insufficiency. Lymphatic vessels function as multicellular signal-processing systems in which receptor activity is context dependent and continuously modulated by ligand availability, tissue stiffness, inflammatory tone, and metabolic state. Under therapeutic stress, receptor systems that are secondary under homeostatic conditions, including mechanosensitive ion channels, purinergic receptors, and stress-responsive G protein-coupled receptors, can exert disproportionate influence over endothelial transcription, barrier function, contractile coordination, and immune-vascular feedback loops. Sustained activation of these networks may reinforce inflammatory and remodeling programs, providing a mechanistic explanation for delayed onset, nonlinear progression, and interindividual variability. This signaling-centered framework positions lymphatic failure after cancer therapy as a disorder of network integration and identifies stress-responsive receptor systems as tractable points for early intervention.