Targeting SND1 To Enhance Dendritic Cell Reprogramming For Cancer Immunotherapy

Reprogramming cancer cells towards type I dendritic cells (iDC1 reprogramming) – is a promising novel approach to cancer immunotherapy to address defective tumor antigen presentation and insufficient T-cell activation. However, epigenetic barriers may hinder lineage commitment, reducing conversion efficiency and maturation, highlighting the need to identify factors that impede cell reprogramming. Our prior CRISPR/Cas9 screening has identified key epigenetic regulators affecting human fibroblast reprogramming to DC1. Among these, SND1 emerges as an underexplored barrier that serves as a global regulator in transcriptional and post-transcriptional gene expression in direct cell reprogramming. Hence, this study investigates the impact of SND1 on the iDC1 reprogramming machinery in murine cancer cells, aiming to enhance reprogramming efficiency and tumor immunogenicity. Using CRISPR/Cas9 to target SND1, cells underwent DC1 reprogramming via lentiviral-mediated delivery of PU.1, IRF8, and BATF3 transcription factors, followed by characterization of DC1-specific markers and antigen-presenting signatures to evaluate their reprogramming efficiency upon SND1 depletion. Furthermore, the impact of SND1 deficiency in DC1-like cells in controlling tumor growth and mouse survival following in vivo DC1 reprogramming was assessed in mouse models. Additionally, a clinically translatable adjuvant targeting SND1 was tested to synergize DC1 reprogramming to dissect the time-dependent role of SND1 in DC1 reprogramming. Our findings reveal SND1 depletion in tumor cells not only enhances DC1 maturation but also significantly upregulates MHC-I levels in B16 and YUMM1.7 melanoma cell lines. More strikingly, SND1 depletion efficiently boosts hard-to-treat melanoma therapy in mice, improving survival via enhanced proportion of DC1 cell reprogramming and functional DC1 cells with increased IL-12 secretion. This suggests iDC1 reprogramming upon SND1 inhibition would translate to elicit stronger cytotoxic anti-tumor responses against melanoma tumors. More excitingly, pretreatment with an SND1 inhibitor synergizing with DC1 immunotherapy holds translational potential to amplify iDC1 reprogramming outcomes in future clinical trials.