A new study in Cell Death & Discovery reports that fibronectin 1 can drive gastrointestinal stromal tumor (GIST) progression by promoting histone lactylation—an extracellular-matrix linked epigenetic mechanism. The work connects the tumor microenvironment to chromatin chemistry, highlighting a pathway that could be exploited for more selective GIST therapies. In parallel, a new review in Medical Oncology argues that the traditional view of ATP-binding cassette (ABC) transporters as simple drug efflux pumps is incomplete. It frames how transporter activity also supports leukemia drug resistance through cellular adaptation to the microenvironment. Together, the findings reinforce a growing theme in oncology: resistance and aggressiveness are increasingly understood as multi-layer biology spanning extracellular cues, chromatin modifications, and stress-adaptive programs—each a potential lever for next-generation therapeutics.