PurposeThe identification of robust predictive biomarkers of the response to programmed cell death-1 (PD-1) blockade remains a critical concern. Here, we investigated on fibroblast activation protein (FAP) as a microenvironment-derived biomarker of clinical outcomes of PD-1 blockade therapy, and the correlation between FAP expression and T cell infiltration in advanced non-small cell lung cancer (NSCLC).MethodsA total of 135 patients with advanced NSCLC who received PD-1 blockade therapy were retrospectively analyzed. The potential associations among FAP expression, CD3 + T cell and CD8 + T cell infiltration, and clinical outcomes of immunotherapy were validated by immunohistochemistry, bioinformatic analyses, and statistical measurements.ResultsFAP was widely expressed in advanced NSCLC tissues. FAP was correlated with decreased density of CD8 + T cells (Spearman’s rho  – 0.32,p< 0.001) and immunosuppressive tumor microenvironment (TME) status. No correlations were detected between FAP and PD-L1 expression or with the density of CD3 + T cells. The patients with higher expression of FAP showed worse response rate (16.4%vs.38.7%,p< 0.001) and worse progression-free survival (HR = 2.56, 95% CI 1.69–3.87,p< 0.001). In addition, FAP contributed to shortened overall survival in subgroups of the patients with squamous cell lung cancer (p= 0.020), PD-1 blockade monotherapy (p= 0.017), and first-line therapy (p= 0.028).ConclusionFAP is a potential predictive biomarker of resistance to PD-1 blockade. Further investigation is warranted to identify a strategy for targeting FAP to alleviate the immunosuppressive TME and broaden the clinical effectiveness of PD-1 blockade therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-022-04250-4.