Semaphorin Signaling in Nervous System and Cancer Dynamics

Semaphorins comprise a large family of secreted and membrane-anchored proteins that were first characterised as axon guidance factors in the developing nervous system. They act through plexin and neuropilin co-receptors to direct growth cone collapse, neuronal migration and synaptic organisation. Beyond neural patterning, semaphorin pathways have emerged as critical modulators of vascular development, immune cell trafficking and tumour biology. In cancer, semaphorins influence angiogenesis, lymphangiogenesis, tumour cell proliferation, invasion and the infiltration and function of immune effector cells. Crosstalk between semaphorin signalling and other receptor tyrosine kinase pathways further shapes tumour progression and resistance to therapy. Together, these findings highlight semaphorin–plexin axes as nodes linking nervous system development, immune regulation and oncogenesis, with therapeutic implications for neurodegenerative disorders, fibrosis and malignancy.

Research from Nature Portfolio

Recent studies have demonstrated that tumour-derived Semaphorin-3A engages Neuropilin-1 and Plexin-A receptors on activated CD8+ T cells to induce F-actin collapse, impair immunological synapse formation and inhibit T-cell motility. Genetic ablation of Neuropilin-1 in T cells or pharmacological blockade of the Sema3A–Neuropilin-1 axis enhances CD8+ infiltration into solid tumours, restricts tumour growth in preclinical models and correlates with improved survival in patient cohorts. These findings establish a direct role for semaphorin signalling in immune suppression within the tumour microenvironment and suggest that targeting this pathway may potentiate cancer immunotherapy.

Semaphorin Signaling in Nervous System and Cancer Dynamics publication trend

The graph below shows the total number of articles in semaphorin signaling in nervous system and cancer dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Semaphorin: A family of secreted or membrane-bound proteins that guide neuronal axons and regulate cell migration through receptor complexes.

Plexin: A family of high-affinity semaphorin receptors whose cytoplasmic domains transduce signals to Rho-family GTPases.

Neuropilin: A co-receptor for class-3 semaphorins (and certain growth factors) that confers ligand specificity and modulates plexin activation.

Growth cone collapse: The rapid retraction of actin-rich protrusions at the tip of a developing neurite in response to repulsive guidance cues.

Angiogenesis: The formation of new blood vessels from existing vasculature, a process often co-opted by tumours to secure oxygen and nutrients.

Rac1: A small GTPase that regulates actin cytoskeleton dynamics, cell migration and survival signalling downstream of semaphorin–plexin interactions.

References

1. Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells. Nature Communications (2024).
2. Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression. International Journal of Molecular Sciences (2019).
3. Structural Basis for Plexin Activation and Regulation. Neuron (2016).
4. Sema3C Promotes the Survival and Tumorigenicity of Glioma Stem Cells through Rac1 Activation. Cell Reports (2014).