Schwann cells as immunomodulators in the tumor immune microenvironment: Mechanisms and therapeutic implications.

Schwann cells (SCs), the predominant glial cells in the peripheral nervous system (PNS), are increasingly recognized as crucial modulators of the tumor immune microenvironment (TIME). In response to tumor-derived signals, SCs undergo repair-like phenotypic reprogramming and regulate TIME immune cells by secreting chemokines, cytokines, immunomodulatory lipids, and remodeling the tumor metabolic milieu. Their immunomodulatory activity exhibits context-dependent duality: SCs promote tumor progression in pancreatic cancer (via CCL2-mediated TAM polarization), melanoma (via COX-2/PGE2-induced T cell suppression), lung cancer (via M2 macrophage polarization), breast cancer (via CXCL2-mediated pain and immunosuppression), colorectal cancer (via COX-2/PGE2-driven immunosuppression), and cervical cancer (via PACAP-facilitated perineural invasion); while they suppress tumor growth in early pancreatic cancer (via sympathetic innervation-enhanced anti-tumor immunity) and specific stages of neuroblastoma (NB, via anti-angiogenic factors including SPARC and PEDF). Beyond immune modulation, SCs influence tumor neuroinvasion, pain, and angiogenesis, further shaping tumor progression. The intricate SC-TIME interplay presents novel therapeutic avenues: preclinical and clinical evidence supports strategies including modulating SC activation, selective SC depletion, interrupting SC-TIME interactions, and supplementing SC-derived factors. For instance, modulating SC activation shows promise in pancreatic ductal adenocarcinoma preclinical models, and SC-derived anti-angiogenic factors are a potential strategy for NB therapy-with several approaches advancing to clinical trials or securing approval. Critical challenges persist, including clarifying SC functions in distinct tumor microenvironments and developing selective interventions that target SCs' tumor immunoregulatory roles without impairing their normal PNS physiology. Nevertheless, targeted modulation of SC-mediated immunomodulation may pave the way for enhancing cancer immunotherapies and improving patient outcomes.