Impact of miR-30d on Cancer cell and Tumour Microenvironment Crosstalk

Cancer progression is driven not only by mutations within tumour cells but also by their reciprocal interactions with the tumour microenvironment. In healthy tissues, the extracellular matrix, nutrient limitations, and immune surveillance maintain homeostasis and suppress malignant transformation. As cancer evolves, tumour cells progressively corrupt this protective environment. With time, as oncogenic programs are induced, crosstalk between tumour cell and stromal components residing in the tissue environment promotes activation of CAFs, ECM remodelling, abnormal angiogenesis, and immune suppression, collectively establishing a tumour permissive niche. Key oncogenic drivers such as mutp53, HIF, and YAP/TAZ respond to stromal cues like hypoxia and ECM stiffening to reinforce these pro‑tumourigenic changes. Understanding how these pathways contribute to poorly immune‑infiltrated tumours, associated with limited response to immune checkpoint blockade, is essential for improving the efficacy of anticancer therapies. Notably, mutp53, HIF and YAP/TAZ can promote immune evasion by dampening the cGAS/STING/IFN‑I pathway, a central innate immune axis required for effective anti‑tumour immunity. We have previously demonstrated that mutp53-induced overexpression of the onco-miRNA miR-30d in invasive breast cancer cells promotes the release of a pro-malignant secretome, modifies the TME, ultimately promoting tumour growth and accelerating metastasis. miR-30d level is frequently found elevated in BC and other solid tumours and its role in late‑stage disease is established, but its contribution to the earliest phases of tumourigenesis remains largely unexplored. Through my phD project, I am investigating how miR-30d influences the TME using a cellular model of pre-invasive breast ductal carcinoma in situ (DCIS). The findings revealed that miR-30d level is already high in this early breast cancer (BC) model, where it can actively suppress innate immune signalling by attenuating the cGAS/STING/IFN-I cascade. Notably, inhibition of miR-30d by specific Locked nucleic acid or Decoy inhibitors both triggers upstream induction and favors the execution of the pathway in BC cells, while not in normal breast epithelial cells. Mechanistically, miR-30d preserves nuclear envelope integrity, thus controlling cytosolic release of cGAS-inducing dsDNA, and preventing TREX1 nuclear entry and genomic DNA damage. This effect was largely attributed to the ability of miR-30d to sustain Lamin B expression through the LATS2/YAP axis. Specifically, miR-30d was found to inhibit LATS2, thus activating YAP and driving expression of Lamin B and other NE components. In parallel, miR-30d inhibition restores the ER–Golgi trafficking of STING, by normalizing secretory pathway function. Across BC cell lines, patient-derived organoids and in cell lines derived from different tumour types, miR-30d inhibition leads to robust activation of the cGAS/STING pathway, causing secretion of type-I IFN and cGAMP. In turn, cGAS/STING activation consequent to miR-30d blockade also suppresses proliferation and induces STING-dependent apoptosis of cancer cells, synergizing with DNA-damaging agents such as doxorubicin and with CDK4/6 inhibitors. In immunocompetent mouse models of BC, miR-30d inhibition enhances NK and CD8⁺ T cells infiltration, suppresses tumour growth, and sensitizes resistant tumours to ICB therapy. Consistently, analysis of publicly available tumour gene expression datasets revealed a strong inverse correlation between miR-30d activity and anti-tumour immunity in BC patients’ samples, suggesting that elevated miR-30d levels are associated with an immune-cold, poorly infiltrated TME, and with limited immunotherapy response.