Abstract

Intraoperative fluorescence-guided surgery is an important adjunct to brain tumor resection. However, fluorescent probe performance varies across molecularly and histopathologically distinct entities, including IDH-wildtype glioblastoma, metastatic brain tumors (MBTs), and primary central nervous system lymphoma (PCNSL), and the mechanisms underlying this variability remain poorly understood. We propose a mechanistic framework integrating biomechanical constraints, molecular barrier heterogeneity, and probe-specific pharmacokinetics to explain cross-tumor differences in fluorescence signal. Probe performance is conceptualized through three sequential bottlenecks: extravasation (blood–brain barrier/blood–tumor barrier permeability and transcytosis), interstitial penetration (extracellular matrix density and hydraulic resistance), and retention/clearance (efflux transporters and metabolic processing). An overlying optical layer, including tissue absorption, scattering, and autofluorescence, further modulates the detected signal. Tumor-specific molecular heterogeneity critically shapes these processes. In IDH-wildtype glioblastoma and legacy high-grade glioma cohorts, heterogeneous expression of ATP-binding cassette transporters has been associated with reduced intracellular accumulation of protoporphyrin IX after 5-aminolevulinic acid administration and may contribute to false-negative fluorescence in selected tumor regions. In MBTs, stage-dependent blood–tumor barrier integrity and vascular programs influence probe delivery, whereas in PCNSL, corticosteroid-sensitive restoration of endothelial barrier function may compromise the performance of leakage-dependent tracers. Together, this framework highlights how tumor biology, barrier function, and probe pharmacology jointly shape fluorescence contrast. Rational probe selection informed by tumor-specific transport and barrier constraints may improve intraoperative visualization of brain tumors and optimize surgical decision-making.

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