Background <p>The utilization of immune checkpoint blockade has shown limited effectiveness in individuals with glioblastoma (GBM). GBM remains highly resistant to conventional therapeutic interventions such as surgical resection, chemoradiotherapy, and tumor-treating fields, and its recurrence is nearly inevitable, leading to a poor prognosis. The efficacy of anti-PD-1 therapy in recurrent GBM (rGBM) is inconsistent, and there is a lack of reliable predictive biomarkers for immunotherapy.</p> Methods <p>In this prospective exploratory study, we assessed the correlation between Interleukin-32 (IL-32) expression and therapeutic outcomes, namely progression-free survival (PFS) and overall survival (OS), in patients with recurrent, surgically resectable GBM. These patients were administered neoadjuvant therapy consisting of an anti-PD-1 antibody in combination with an anti-angiogenic agent as part of the treatment regimen for rGBM.</p> Results <p>In the cases we studied, patients with recurrent glioblastoma (rGBM) and elevated IL-32 expression had a significantly longer survival time than those with lower IL-32 levels. This suggests that IL-32 may play an important role in the prognosis of rGBM patients.</p> Conclusions <p>Our study identifies a distinctive “IL-32 paradox”: while typically associated with poor prognosis in the general glioma population, high IL-32 expression is associated with a favorable response to neoadjuvant anti-PD-1 and anti-angiogenic therapy. This suggests that IL-32 serves as a candidate biomarker associated with the “hot” immune microenvironment required for this combination regimen.</p>