Unraveling the complexity of JAK-STAT signaling in cancer

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a central mediator of cytokine and growth factor signaling, governing key cellular processes including proliferation, differentiation, survival, and immune regulation. Comprising four JAK family members (JAK1, JAK2, JAK3, TYK2) and seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6), this pathway enables rapid transmission of extracellular signals directly to the nucleus, bypassing many intermediary amplification steps required by other signaling cascades. Dysregulation of JAK-STAT signaling is now recognized as a hallmark of numerous malignancies, contributing to tumor cell survival, immune evasion, and therapeutic resistance. While the clinical success of JAK inhibitors highlights the pathway’s therapeutic potential, it has also revealed the profound context dependency of JAK-STAT signaling across cancer types and disease stages.Despite decades of investigation, the JAK-STAT pathway continues to reveal unexpected layers of complexity. Individual STAT proteins can function as oncogenic drivers in some contexts while exerting tumor-suppressive effects in others, underscoring the importance of cellular and microenvironmental context. Beyond sustaining intrinsic tumor cell signaling, cancer cells co-opt the JAK-STAT pathway to remodel the tumor microenvironment by suppressing cytotoxic lymphocyte activity, promoting the recruitment of immunosuppressive myeloid populations, and facilitating resistance to immune checkpoint blockade. Recent technological advances, including single-cell and spatially resolved profiling, have enabled unprecedented insight into the heterogeneity of JAK-STAT activation within tumors. At the same time, emerging therapeutic strategies—ranging from selective STAT inhibitors to targeted protein degraders—highlight the urgent need for a more precise mechanistic understanding of pathway components and their context-specific roles.This Research Topic aims to integrate cutting-edge basic, translational, and clinical research to advance our understanding of JAK-STAT signaling in cancer and to inform the development of more effective therapeutic strategies.We welcome Original Research, Systematic Reviews, Reviews, and Mini-Reviews addressing, but not limited to, the following themes:- Context-dependent oncogenic and tumor-suppressive roles of individual STAT proteins across cancer types.- Crosstalk between JAK-STAT signaling and other oncogenic pathways, including PI3K/AKT, MAPK, NF-κB, and Wnt.- Mechanisms of JAK-STAT-mediated immune evasion and modulation of the tumor microenvironment.- Resistance mechanisms to JAK-targeted therapies and strategies to overcome them.- The role of JAK-STAT signaling in cancer stem cells, cellular plasticity, and lineage reprogramming.- Emerging therapeutic approaches, including selective STAT inhibitors, targeted protein degraders, and rational combination therapies with immune checkpoint blockade.- Translational and clinical insights, including biomarkers of pathway activation and strategies for patient stratification.Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Manuscripts focusing solely on cost-effectiveness studies are also not considered for publication in this journal. Topic editors: Bernhard Zdársky, Xiu-Qiong FU Source: https://www.frontiersin.org/research-topics/83429/unraveling-the-complexity-of-jak-stat-signaling-in-cancer