Glioblastoma in the post-2021 era: Diagnostic recalibration, therapeutic innovations, and future horizons

Table 3 Strategies, opportunities, and reframing challenges

Strategy/modality	Therapeutic rationale	Key challenges and barriers	Research directions
CAR-T/cell immunotherapy	Engineered T cells targeting tumor antigens	Antigen heterogeneity, neurotoxicity, manufacturing, infiltration	Multivalent/armored constructs, locoregional dosing, repeat infusions
Checkpoint inhibitors/immunotherapy	Release immune suppression	Cold tumor microenvironment, low TMB	Combination therapies, microenvironment modulation, biomarker selection
Vaccines and oncolytic viruses	Prime systemic/Locoregional immune responses	Delivery, immune suppression, limited by scale	Combinatorial adjuvants, intratumoral delivery, optimized scheduling
TTFields	Disrupt mitosis and sensitize cells	Compliance, cost, modest benefit	Synergy with immunotherapy, biomarker-guided use
Liquid biopsy	Dynamic molecular monitoring	Low sensitivity, compartmentalization	Improved assay sensitivity, integration into adaptive trials
Spatial profiling/single-cell	Map heterogeneity and niche interactions	Data complexity, translation to therapy	Use to guide trial designs and antigen selection
Adaptive and platform trials	Efficient evaluation across arms	Statistical complexity, regulatory harmonization	Master protocols, biomarker stratification, real-time adaptive arms

TMB: Tumor mutational burden; TTFields: Tumor treating fileds; CAR-T cell: Chimeric antigen receptor T cell.