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<p>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&#xa0;mediator of invasive immune resistance and support NGFR inhibition as a strategy to enhance immunotherapy efficacy.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月26日

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  • Laura Nogués,
  • Vanesa Santos,
  • Juan García-Agullo,
  • Susana García-Silva,
  • Oscar Maiques,
  • Alberto Hernández-Barranco,
  • Marina S Mazariegos,
  • Manuel Pérez-Martinez,
  • Raúl Torres-Ruíz,
  • Annalisa Saltari,
  • Patrick Turko,
  • María Mannino,
  • Ali Nejatie,
  • Hassan Nassour,
  • Diego Megías,
  • Isabel Peset,
  • Carmen Blanco-Aparicio,
  • Sonia Martínez,
  • Mitchell Levesque,
  • H Uri Saragovi,
  • Victoria Sanz-Moreno,
  • Héctor Peinado

摘要

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.