Spatially fractionated radiotherapy: Integrated dose heterogeneity and radiobiology for bulky tumor

Table 1 Summary of dual radiobiological pathways and clinical implications of spatially fractionated radiotherapy

Mechanism category	Specific pathway	Biological description	Clinical implication
Normal tissue preserving	Partial volume effect	Interspersed low-dose “valleys” preserve functional subunits within normal tissues, allowing rapid cellular repopulation and repair	Significantly reduces acute and late toxicity, enabling the safe escalation of “peak” doses for previously untreatable bulky tumors
Local antitumor effects	Bystander effect	Cytotoxic stress signals (e.g., TNF-α, TRAIL) released from high-dose “peaks” induce secondary apoptosis in neighboring cell populations residing in the “valleys”	Expands the effective cytocidal zone within the tumor mass beyond the physically irradiated high-dose regions
Local antitumor effects	Vascular disruption	High-dose focal beams cause severe microvascular endothelial cell damage mediated by ceramide signaling	Results in vessel occlusion, leading to subsequent ischemic necrosis of centrally located, radioresistant tumor segments
Systemic antitumor effects	Immunogenic cell death (abscopal effect)	Massive cell death releases tumor antigens and danger-associated molecular patterns, recruiting antigen-presenting cells to prime adaptive immune response	Offers potential for synergistic out-of-field lesion regression and highlights a strong rationale for combination with systemic immunotherapy regimens

TNF-α: Tumor necrosis factor-alpha; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand.