Emotional distress impairs immune checkpoint blockade efficacy in recurrent high-grade glioma: Insights from tumor in situ fluid analysis

Abstract Background Immune checkpoint blockade (ICB) therapy has shown limited benefit in recurrent high-grade glioma (HGG), in part due to an immunosuppressive tumor microenvironment. Emotional distress (ED) is known to alter immune regulation, yet its role in shaping the response to ICB in glioma remains unexplored. We aimed to determine the association between pre-treatment ED and ICB efficacy in recurrent HGG (rHGG) and to explore the underlying mechanism using tumor in situ fluid circulating tumor DNA (TISF-ctDNA). Methods We prospectively enrolled 75 rHGG patients receiving tislelizumab, bevacizumab, and temozolomide. ED was evaluated using PHQ-9 and GAD-7 before undergoing ICB treatment. Clinical outcomes were compared between ED and No ED groups. TISF-ctDNA sequencing and immunohistochemical staining of tumor tissues were performed to identify pathway alterations and immune markers. Results Compared to No ED patients, ED patients had significantly shorter overall survival (15.8 vs. 32.3 months; HR = 2.40, P = .006) and progression-free survival (3.4 vs. 7.8 months; P = .049), along with lower objective response (10.7% vs. 48.5%, P = .002) and clinical benefit rates (39.3% vs. 69.7%, P = .017). TISF-ctDNA analysis revealed enrichment of AXON guidance, cAMP signaling, and HPV-related pathways in ED patients. ED was also associated with elevated systemic inflammatory markers (NLR, MLR, PLR; P < .05). IHC showed decreased infiltrating immune cells in tumors from ED patients. Conclusions Pretreatment ED is associated with impaired ICB efficacy in rHGG, potentially mediated by altered tumor signaling and reduced intratumoral immune cell infiltration. Psychological screening may enhance personalized immunotherapy strategies.