NGFR induces melanoma invasion and immunotherapy resistance through myosin light chain 2 modulation

Immunotherapy has reshaped melanoma treatment, yet the majority of patients fail to respond or develop resistance. Nerve growth factor receptor (NGFR/p75NTR/CD271) has been linked to melanoma aggressiveness and therapeutic resistance, but the underlying mechanisms remain unclear. Here, we demonstrate that pharmacologic inhibition of NGFR with THX-B significantly reduces distant metastasis and restores sensitivity in immunotherapy-resistant tumors. THX-B treatment also enhances intratumoral CD8⁺ T-cell infiltration. Further, we show that immune-resistant melanomas acquire an invasive, ameboid phenotype characterized by elevated NGFR, PD-L1, and activation of non-muscle myosin light chain 2 (NM II; MLC2). Mechanistically, NGFR regulates RhoA/ROCK-dependent MLC2 phosphorylation and proteasomal stabilization. Analysis of melanoma patient samples reveals that high NGFR expression correlates with reduced progression-free survival following immunotherapy. Moreover, NGFR and phosphorylated MLC2 are consistently enriched at the invasive fronts of primary tumors, metastases, and in immunotherapy-resistant cell lines from melanoma patients. Altogether, these findings identify the NGFR-MLC2 axis as a mediator of invasive immune resistance and support NGFR inhibition as a strategy to enhance immunotherapy efficacy.