Sema3A has received less focus than its receptors. The study of Sema3A and its receptors, such as plexinsA1-A4 (PLXNA1-A4) and neuropilin-1 (NRP1) in PC, demonstrates that SEMA3A had no impact on the growth or survival of pancreatic tumor cells and was upregulated in PC. Its signaling might partially mediated by Rac1 (12). Interestingly, one research study composed a novel type of hybrid peptide, Sema3A-lytic, which is be formed of two functional amino acid domains: a sequence that binds to NRP1 from Sema3A and a cytotoxic lytic peptide. In addition, this hybrid peptide shows that the Sema3A-lytic hybrid peptide would be a possible anti-cancer agent for treating human PC (13). This may provide a new idea for subsequent studies.

Sema3B, as a potential tumor suppressor gene, gene loss or down-regulation of its function can promote tumor progressions, such as in lung cancer, breast cancer, ovarian cancer, liver cancer, and cholangiocarcinoma (14–17). Plexins are essential receptors for Sema3B activation of downstream signaling pathways, and Sema3B function depends on the NRP receptor to provide binding sites for both receptors. This can exert anti-tumor angiogenesis and promote tumor cell apoptosis through specific binding to the high affinity of both receptors. Sema3B can compete with VEGF for NRP receptors, hindering the promoting effect of VEGF on vascular endothelial cell division, and partly inhibiting angiogenesis. Thus, it indirectly blocks the nutrient supply of tumor cells and slows down cell division (18). Gao (18) et al. shows that lentiviral vector transfection can construct a stable Sema3B upregulated model in PC CFPAC-1 and PANC-1 cell lines. Overexpression of Sema3B could significantly inhibit the proliferation, invasion, and migration of CFPAC-1 and PANC-1 cells, which means that Sema3B may have an essential role in inhibiting tumor genesis and development in PC. The expression level of Sema3B in PC tissues is closely related to the PC tumor stage, local invasion, lymphatic metastasis, and distant metastasis, and the expression level of Sema3B in PC tissues is closely related to the degree of malignancy of PC. The lower the Sema3B expression level, the higher the pathological malignancy of PC. However, due to the few studies on Sema3B in PC, its specific molecular mechanism still needs to be elucidated.

Sema3C has a role in promoting tumor development (19), and it is hypomethylated, and its expression increases with tumor progression (20) in PC. Xu (21) et al. suggested that abnormal expression of Sema3C is associated with poor prognosis in patients with PDAC, and high Sema3C expression in PC was associated with a shorter survival time (22). Sema3C may promote PC cell migration and invasion by inducing the epithelial-mesenchymal transition (EMT) and may contribute to cancer therapy. The extracellular signal-regulated kinase (ERK)1/2 is the most critical pathway for promoting cell proliferation, metastasis, and EMT during tumorigenesis. Sema3C promoted the phosphorylation of ERK in PC and confirmed that Sema3C mediated cell proliferation in PC both in vitro and in vivo. Furthermore, Proliferation, migration, invasion, and EMT in a PC cell line attenuated and PDAC cell tumorigenesis upon after xenotransplantation into nude mice reduced since Sema3C was knockdown. Overexpression of Sema3C had the contrary effects and boosted the ERK1/2 signaling pathway (21). Furthermore, the combination of trametinib (MEK inhibitor, downstream of KRAS) and Sema3C inhibitor can induce a synergistic effect in KRAS G12D cells, which shows Sema3C might be a potentially prospects and attractive target for PC therapy, especially in patients with G12D mutation in KRAS (22). These features suggest the strong potential of Sema3C in the treatment of PC.

Sema3D and its receptor PlexinD1 (PlxnD1) are particularly interesting, as they are the part that is frequently amplified and mutated in human PDA. Jurcak (23) et al. found that the invasive and metastatic capacity of PDA cells is increased due to the interaction of Sema3D with its co-receptors PlxnD1 and Neuropilin-1. It is supported in another study (24) that tumor cells expressing Sema3D can travel toward PlxnD1-expressing neurons, according to their Diagnosis Related Groups (DRG) in vitro data. However, the molecular mechanism of Sema3D in assisting increased PDA cell invasion and metastasis is unknown. Interestingly, this increase of glycolytic gene expression was inhibited with the neutralizing antibody PlexinD1. They also suggested that Sema3D signaling pathway could offer another selectivity in mutant Kras cells.

Moreover, Sema3D in PC is interesting in the conduction relationship between Sema3D, Annexin A2 (AnxA2), and PlexinD1. Foley (25) et al. elucidated one mechanism of PDA metastasis formation: Sema3D can bind to PlxnD1 on the surface of PDA tumor cells in the extracellular space by the regulation of its autocrine function control of AnxA2. This mechanism has also been proven to promote the invasion and metastasis of PDA cells (26) and the tumor. Mice carrying PDA prolong survival and reduces metastasis due the knockdown of Sema3D (24). These studies increase therapeutic options in PDA and provide a strong rationale for the development of adjuvant therapies targeting AnxA2 and Sema3D for PDA after local resection (26).

Unlike the other three classes of signaling elements, Sema3E can directly bind to its receptor, PlxnD1, which activates cellular signaling. This combination has been shown to contribute to the aggressive and metastatic spread of cancer cells. Lin et al. have shown that Sema3E was significantly expressed in the nuclei of PC cells and overexpressed in human PC which was associated with tumor progression and poor survival (27, 28). Also, they have shown that overexpression of Sema3E in PC cells promoted cell proliferation and migration in vitro, while cancer cell proliferation and migration in vitro had the opposite function (27). In other words, higher incidence and growth of tumors were exhibited by Sema3E overexpressed cells (28), whereas they were reduced by Sema3E knockout cells. Moreover, Sema3E induces cell proliferation through MAPK/ERK pathway (28) ( Figure 1 ). Therefore, Sema3E may be a suitable prognostic marker and an attractive new therapeutic target. It has been confirmed in a study (29) that Sema3E is significantly upregulated after therapeutic expression of panc28 cell lines and is one of the common biomarkers.

Interestingly, the ADAMTS9-AS1-SEMA3G pathway is predicted to play an essential role in immune cell regulation by database screening and validation (30). TCGA and GEO databases were analyzed to screen differential lncRNA ADAMTS9-AS1 associated with prognosis. GO and KEGG enrichment analyses were performed, and the results showed that the gene was significantly associated with immunity. The infiltration, significant positive correlation with B cells, CD4⁺ T cells, CD8⁺ T cells, neutrophils, macrophages, and dendritic cells (DCs) was verified using the TIMER database, and a more significant correlation with CD8⁺ T cells and macrophages in PC. Negative correlation between the lncRNA and tumor grade was shown in a clinical correlation analysis. Thus, it shows that the higher the lncRNA expression in PC, the more immune infiltration in the tumor, the lower the tumor grade, and the better the patient prognosis (30). Therefore, the ADAMTS9-AS1-SEMA3G pathway is predicted to play an essential role in immune cell regulation.

Additionally, Gao (31) et al. have proven the role of Sema3G in proliferative capacity and cell migration in PC cells. Human PC PANC-1 cells were transfected with the Sema3G lentivirus interference vector, whose proliferation, invasion, and migration capacity were significantly decreased, indicating that Sema3G could significantly inhibit the proliferation, invasion, and migration of PC. The mechanism of Sema3G inhibiting PC invasion and metastasis and the signaling pathways it works with to inhibit PC progression still needs further intensive investigation.

Sema4D has been one of the research hotspots in recent years. It has been deemed to promote the progress of malignancies by affecting cell proliferation, apoptosis, and immigration (32). Sema4D can bind to the ligand Plexin-B1 and activate small GTPase Ras homolog gene family, member A (RhoA), causing the phosphorylation of MAPK and Akt, thereby enhancing the invasive energy of PC cells (33, 34) ( Figure 1 ). It was reported in the relevant literature that inhibition of Sema4D in tumor cells not only inhibits tumor angiogenesis but also may restore T-cell immune activity specific to antigens (34, 35). Notably, Sema4D-siRNA downregulates the expression of Sema4D in pancreatic cells, inhibiting the proliferation of PC cells and reducing their invasive ability and apoptosis (36). Therefore, a team proposed immunotherapy strategies to block Sema4D, which could improve the sensitivity of PDAC to immune checkpoint blockade (ICB) (37), and treatment with Sema4D blocking antibody improved response to ICB in combination by using the standard of care FOLFIRINOX in preclinical murine studies (38). Moreover, the considerable progress of Pepinemab, the Sema 4D antibody, is well tolerated and has potent anti-tumor activity (39), but resistance to immunotherapy often limits patient efficacy. It has been suggested in studies that when Sema4D antibodies are combined with immune checkpoint inhibitors, such as the anti-Sema4D antibody Pepinemab, and combined with the immune checkpoint inhibitor PD-L1 mAb Avelumab, they can enhance T-cell activity, thus persistently inhibiting tumor growth (40).

Sema5A is tumor-promoting in PC. Moreover, Sema5A is expressed in most PC tissues and is not or low expressed in normal pancreatic tissues, which elucidates that Sema5A could be a marker for PC (41, 42). Furthermore, upregulation of mouse Sema5A in Panc1 enhanced tumor cell proliferation and the incidence of distant metastasis to the lymph nodes, liver, spleen, and peritoneal cavity after in situ injection in mice. It was suggested by these results that Sema5A was associated with tumor growth, metastatic potential, and invasiveness (43). It is noteworthy that PC cell migration is enhanced by Sema5A by activating cMet signaling in a PlexinB3-dependent manner (44) ( Figure 1 ). Additionally, proliferation and angiogenesis are promoted by SEMA5A in the primary tumor setting, thereby enhancing metastasis (44, 45). Thus, Sema5A/PlexinB3 may represent an attractive targetable axis in PC.

Sema6C might be a potential tumor suppressor in PC and serve as a poor prognostic biomarker in PC (45). Sema6C, a tumor suppressor in PC, causes reduction of cyclin D1 expression and cell proliferation which includes cyclin-dependent kinase 4/6(CDK4/6) (46) by inhibiting the AKT/GSK3 signaling axis (47) ( Figure 1 ). Moreover, they demonstrated a brand new regulatory role of miR-124-3p in suppressing Sema6C and suggested the treatment of Sema6C-downregulated cancer by CDK4/6 inhibitors (48).