Crosstalk between NRP1 and autophagy in the tumor microenvironment: from molecular mechanisms to therapeutic targeting

Neuropilin-1 (NRP1) is overexpressed in various malignant solid tumors, modulating the tumor microenvironment (TME) via multiple mechanisms to promote immune suppression, angiogenesis, and epithelial-mesenchymal transition (EMT), ultimately resulting in poor patient survival. Autophagy, a highly conserved cellular self-degradation process, plays a stage-dependent, bidirectional role in cancer. At early stages it suppresses tumorigenesis by clearing damaged cellular components, whereas at advanced stages it supports tumor survival under stress and thereby enhances proliferation, invasiveness, and therapy resistance. The interplay between NRP1 and autophagy in the TME is characterized by reciprocal regulation: NRP1 activates certain pathways to regulate autophagy, whereas autophagy induction promotes NRP1 degradation. This bidirectional interplay directly governs tumor progression and therapy resistance. Although prior studies have provided some clues about their interaction, the regulatory network and the precise mechanisms linking NRP1 and autophagy in the TME remain incompletely characterized. Precision therapies targeting the NRP1-autophagy axis still face multiple obstacles. This review synthesizes data from the atlas cancer genome (TCGA), the genotype-tissue expression (GTEx) database, and the human autophagy database (HADb) to explore associations between NRP1 and autophagy-related gene (ATG) in expression and prognosis, elucidate NRP1-autophagy interaction mechanisms and therapeutic opportunities and challenges in targeting the NRP1-autophagy axis. Pan-cancer analysis showed significant upregulation of NRP1 in 10 solid tumor types and revealed co-expression relationships between NRP1 and 340 ATGs. Among these, co-expression patterns involving genes such as CXCR4 and HSPA5 had significant prognostic value in gastric cancer and glioblastoma. This review systematically explores the panoramic regulatory framework of the NRP1-autophagy axis in the tumor immune microenvironment through bidirectional regulation of activating immunity and inhibitory immunity at the pan-cancer level. It fills the gap in the systematic summary of the NRP1-autophagy axis in regulating the dynamics of the tumor immune microenvironment, and provides a theoretical basis for the clinical translation of combination chemotherapy and immunotherapy targeting the NRP1-autophagy axis.