Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems

The Hallmarks of Cancer framework provided a unifying description of tumor capabilities, but in its static form, it cannot capture where in a tumor these traits occur, when they arise, or how they reorganize under selection pressure. Here, we propose Spatiotemporal Hallmark Ecosystems as a new lens that redefines the functional unit of selection in cancer evolution. In this view, hallmarks are not fixed consequences of mutations but context-dependent phenotypes that are enabled or constrained by local tissue and microenvironmental conditions. This perspective resolves critical paradoxes, explaining why identical mutations yield divergent outcomes, why premalignant states persist without transformation, and how therapeutic resistance emerges not just from clonal selection but also from 'ecological buffering' by the tumor architecture. By shifting the analysis from the individual cell to the ecosystem, we outline a path toward predictive biomarkers and spatially aware strategies that target the structural stability of the tumor.