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

## TL;DR

Emotional distress before treatment is linked to worse outcomes in brain cancer patients receiving immunotherapy, possibly due to changes in tumor signaling and immune cell infiltration.

## Contribution

This study is the first to show that emotional distress impairs immunotherapy response in glioma through tumor in situ fluid analysis.

## Key findings

- Patients with emotional distress had significantly shorter survival and lower response rates to immunotherapy.
- Emotional distress was associated with altered tumor signaling pathways and reduced immune cell infiltration.
- Systemic inflammatory markers were elevated in patients with emotional distress.

## Abstract

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).

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.

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.

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.