The future is not always uniform: rethinking radiotherapy through spatial fractionation

Radiotherapy has traditionally been guided by the principle that uniform delivery of a tumoricidal dose across the entire target volume maximizes local control. However, this paradigm becomes increasingly constrained in the setting of large, bulky or anatomically complex tumours, in which non-malignant tissue tolerances often preclude homogeneous dose escalation. Spatially fractionated radiotherapy (SFRT) has emerged as a complementary approach that introduces intentional intratumoural dose heterogeneity as an alternative therapeutic strategy when uniform irradiation is not feasible. SFRT involves the delivery of radiation as high-dose 'peaks' interspersed with lower-dose 'valleys', creating spatial domains that combine focal tumoricidal exposures with partial preservation of vascular, stromal and immune-related functions within the tumour microenvironment. Preclinical investigations and early clinical studies suggest that such architectures might be associated with rapid volumetric tumour regression, acceptable toxicity profiles and modulation of the tumour immune microenvironment, although the underlying mechanisms, generalizability and durability of these effects remain incompletely defined. In this Review, we summarize the conceptual foundations, biological hypotheses and clinical activity of SFRT, spanning macroscopic approaches such as GRID and lattice radiotherapy, biology-guided strategies and submillimetric implementations using minibeams and microbeams. We also highlight key translational and methodological limitations and discuss various challenges relating to dosimetry, biologically meaningful response assessments, patient selection and multicentre reproducibility.