Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding.

Anoikis, defined as programmed cell death triggered by the loss of cell-extracellular matrix (ECM) and cell-cell interactions, is crucial for maintaining tissue homeostasis and preventing aberrant cell migration. Cancer cells, however, display anoikis resistance (AR) which in turn enables cancer metastasis. AR results from alterations in apoptotic signaling, metabolic reprogramming, autophagy modulation, and epigenetic changes, allowing cancer cells to survive in detached conditions. In this review we describe the mechanisms underlying both anoikis and AR, focusing on intrinsic and extrinsic pathways, disrupted cell-ECM interactions, and autophagy in cancer. Recent findings (i.e., between 2014 and 2024) on epigenetic regulation of AR and its role in metastasis are discussed. Therapeutic strategies targeting AR, including chemical inhibitors, are highlighted alongside a network analysis of 122 proteins reported to be associated with AR which identifies 53 hub proteins as potential targets. We also evaluate in vitro and in vivo models for studying AR, emphasizing their role in advancing metastasis research. Our overall goal is to guide future studies and therapeutic developments to counter cancer metastasis.