Cancer signaling networks in tumor progression and drug resistance: Crosstalk, adaptive reprogramming and therapeutic targeting (Review)

Cancer signaling networks, highly dynamic with interconnected systems, regulate tumor initiation, its progression, therapeutic response and drug resistance. Rather than functioning as isolated pathways, these networks integrate extracellular and intracellular signals through coordinated interactions among membrane receptors, intracellular transducers and downstream effectors. Increasing evidence suggests that pathway crosstalk, feedback regulation and adaptive reprogramming are central to tumor phenotypic plasticity, microenvironmental adaptation and resistance to therapy. In this review, the core architecture of cancer signaling networks and the major oncogenic pathways embedded within them were summarized with a particular focus on PI3K/Akt/mTOR, MAPK/ERK and Wnt/β‑catenin signaling. The dynamic network properties that shape cancer behavior, including compensatory activation, context‑dependent signaling outputs and interactions with the tumor microenvironment, were further discussed. These features provide insights into why single‑pathway inhibition often produces only a limited and transient clinical benefit. Importantly, a network‑level understanding of cancer signaling has major translational implications. Therapeutic resistance frequently arises through pathway reactivation, bypass signaling and adaptive reprogramming, necessitating rational combination strategies and multi‑target interventions. Advances in multi‑omics, single‑cell and spatial technologies and computational modeling are crucial for characterizing signaling network dynamics and identifying clinically relevant vulnerabilities.