Tumor-associated Schwann cells promote salivary adenoid cystic carcinoma stem-like reprogramming via IGF2/IGF1R induced histone H3 lysine 18 lactylation.

Salivary adenoid cystic carcinoma (SACC) is characterized by an exceptionally dense neural network within its tumor microenvironment. Schwann cells (SCs), an essential component of this neural network, have recently emerged as critical mediators of tumor progression. However, SACC-induced SCs reprogramming, as well as the functional significance and molecular mechanisms of tumor-associated Schwann cells (TA-SCs), remains largely elusive. We employed tissue-clearing-based three-dimensional imaging to evaluate the SACC tumor microenvironment with high spatial resolution. We also characterized SCs heterogeneity using single-cell RNA sequencing data from GEO. We investigated the biological phenotypes transformation and revealed the transcriptome characteristics of TA-SCs in SACC, indicating that TGF-β1 exerts its function through c-Jun activation, which is pivotal for driving TA-SCs reprogramming. Furthermore, we determined that TA-SCs enhance SACC cell proliferation, migration, invasion, cisplatin resistance, and stemness. We further discovered that TA-SCs elevate histone lactylation in SACC via paracrine IGF2 signaling. Inhibition of IGF2/IGF1R signaling curbed histone H3 lysine 18 lactylation (H3K18la) in SACC and attenuated the IGF2-driven stem-like reprogramming effect, while simultaneous blockade of TGF-βR1 and IGF1R activation maximally restricted this reprogramming. These findings underscore the pivotal role of TA-SCs in SACC progression and stem-like reprogramming via IGF2/IGF1R-H3K18la axis, representing promising therapeutic targets for this malignancy.