IGF1-IGF1R signaling in tumor-associated macrophages regulates extracellular matrix organization in BRAF inhibitor-targeted melanoma.

Melanoma, particularly driven by activating mutations in the BRAF gene, has witnessed significant therapeutic advances through targeted therapies such as BRAF and MEK inhibitors. However, the development of acquired resistance remains a major clinical challenge, limiting long-term treatment efficacy. The tumor microenvironment (TME), especially tumor-associated macrophages (TAMs), plays a pivotal role in mediating immune evasion, angiogenesis, and drug resistance. Despite extensive research into TAM polarization and function, the precise molecular mechanisms underlying their contribution to therapy resistance remain incompletely understood. Here, we investigated the regulatory role of IGF1-IGF1R signaling in THP-1-derived macrophages and its impact on the sensitivity of co-cultured melanoma cells to the BRAF inhibitor PLX4032. We observed markedly upregulated IGF1 expression in both melanoma cells and THP-1-derived macrophages. Either IGF1R knockdown or pharmacological blockade of IGF1-IGF1R signaling in macrophages restrained the polarization of THP-1-derived macrophages. Both in vitro cellular assays and in vivo xenograft experiments verified that A375 cells pre-co-cultured with IGF1R-deficient macrophages were more sensitive to PLX4032 relative to those pre-co-cultured with IGF1R-proficient macrophages. Transcriptomic analysis reveals that IGF1-IGF1R signaling in THP-1-derived TAMs significantly regulates extracellular matrix (ECM) organization. Collectively, our results offer a new insight into IGF1-IGF1R signaling in THP-1-derived macrophages regulating ECM organization in TME and its potential role in indirectly modifying the tumor cells responsiveness to PLX4032.