Photodynamic therapy (PDT) is an effective oncotherapy and has been approved for clinical application. Unfortunately, its therapeutic efficacy is usually overshadowed by tumor angiogenesis. Thus, a detailed understanding of the tumor angiogenesis upon PDT is imperative. This study aimed to investigate the potential contribution and mechanism of P-21-activated kinase 1 (PAK1) in PDT-induced tumor angiogenesis. Firstly, we found that PAK1 was upregulated upon PDT and associated with tumor angiogenesis. Then, we elucidated the underlying molecular mechanism. Activation of PAK1 prevents hypoxiainducible factor 1 alpha (HIF-1 alpha) protein from ubiquitin-mediated degradation. Thereafter, HIF-1 alpha accumulation results in the upregulation of vascular endothelial growth factor (VEGF), thus promoting tumor angiogenesis. More importantly, we determined that PAK1 knockdown effectually repressed tumor angiogenesis, which contributes to enhance the therapeutic effect of PDT. Together, PAK1 is a potential novel pharmaceutical target for inhibiting PDT-induced tumor angiogenesis, and PAK1 suppression in combination with PDT may be a potentially effective strategy for anti-tumor therapy. (C) 2020 Elsevier Inc. All rights reserved.