Understanding the complexity of the tumor microenvironment through an integrated bioinformatics approach

Cancer is a complex ecosystem evolving through genetic and epigenetic changes in cancer cells and interactions with the tumor microenvironment (TME). Initially tumor-suppressive, the TME later supports tumor growth. a stiff extracellular matrix can promote tumor survival and therapy resistance while impeding immune cell infiltration. Immune checkpoint blockade (ICB) therapy has shown promise for some resistant tumors, particularly "hot" tumors with high immune infiltration. However, "cold" tumors with low immune infiltration often resist chemo-immunotherapies. The cgas/sting1 pathway, which senses cytoplasmic dna and activates interferon responses, plays a key role in anti-tumor immunity. chronic activation can be pro-tumorigenic, while acute activation shows anti-tumor effects. Clinical trials are exploring sting1 agonists in combination with ICB. Understanding these factors could help identify ways to re- sensitize resistant tumors to immunotherapies. My phd lab studied PIN1, an enzyme overexpressed in tumors and linked to therapy resistance. PIN1 uniquely catalyzes prolyl cis/trans isomerization of phosphorylated ser/thr-pro motifs, modulating signal transduction. In breast cancer models, PIN1 inhibition impaired tumor growth and metastasis, enhancing treatment efficacy. This suggests PIN1 is key in promoting a tumor-supporting microenvironment by suppressing anti-tumor immunity. We analyzed transcriptional signatures in breast cancer samples to assess correlations between PIN1 expression, ecm stiffness, and immune cell status. Results showed direct correlation between PIN1 and ecm stiffness, both inversely correlated with anti-tumor immune cells. PIN1 ko cells revealed an increase in both innate and adaptive immune pathways and potential te-derived neoantigens, triggering cd8+ t-cell responses in mice. We investigated how PIN1 inhibition affects the TME using an immune-competent mouse model with conditional PIN1KO. PIN1ko reduced tumor growth and increased immune infiltration. Scrnaseq revealed changes in cancer cells and TME, including fewer cafs and alterations in immune response and cell differentiation pathways. Our results suggest that PIN1 maintains an immunosuppressive TME in bc patients. Inhibiting PIN1 may reduce tumor growth by reprogramming tumor cells and the TME, enhancing immune cell infiltration via ifn pathways.