Cytokines and cancer-associated fibroblasts.

Cancer-associated fibroblast (CAF) is the dominant stromal component within the tumor microenvironment (TME), driving tumor malignancy through complex cell-to-cell communication, with cytokines serving as the fundamental communication medium. In this review, we systematically categorize cytokines into several major families-including interleukins, chemokines, growth factors, tumor necrosis factors, interferons, colony-stimulating factors, and complement system-to delineate their distinct roles in the reciprocal interactions around CAFs, tumor cells, and immune infiltrates. We explore how cytokines function as upstream signals that guide CAF activation and lineage commitment, as well as downstream effectors secreted by CAFs to promote tumor cell malignancy and reprogram the TME. Furthermore, we evaluate therapeutic strategies that target this network by reprogramming CAF functions through blockade of upstream activators or downstream mediators, and by harnessing CAFs for local cytokine delivery. Finally, we address key challenges impeding clinical translation-arising from the pleiotropy, functional redundancy, compensatory feedback loops and spatiotemporal heterogeneity that characterize cytokine signaling networks, as well as from the inherent limitations of current preclinical models-and we outline a theoretical framework for optimizing cytokine-targeted therapies in precision oncology.