Abstract
Lung and colorectal cancers are leading causes of cancer related deaths, often diagnosed at advanced stages. Immunotherapy has significantly improved treatment outcomes for these cancers, but in both cases, a large proportion of patients do not respond to therapy. To improve immunotherapy responses, combining it with drugs that increase cancer immunogenicity is being explored in preclinical and clinical trials. Potential combinations include chemotherapy, DNA damage response inhibitors and innate immune sensors agonists in the aim of enhancing the immune response by increasing neoantigen load and instore an antiviral-like inflammatory reaction.Evaluating the feasibility of these treatments requires an in-depth study of molecular cancer cell immune sensors and the impact of combo-therapies on the tumor and systemic immune response. Thus, my thesis research aims were to:1. Assess the impact of combining immunotherapy, platinum-based chemotherapy, and ATR inhibitors on the immune response in colorectal cancer to achieve long-term disease control.2. Investigate the role of the innate immune sensor STING in different stages of lung cancer progression and its influence on tumor growth and the tumor microenvironment.The first line of research allowed us to identify a combo-therapy in advanced colorectal cancer preclinical models that not only results in tumor eradication in mice but also remodels the immune compartment on a systemic level, determining long term protection to avoid tumor recurrence.The second line of research clarified Sting machinery in different stages of lung cancer progression identifying a tight regulation of the pathway in the cancer cells that results in immune escape and metabolic rewiring dependent on Sting pathway activation.Overall, these results shed light on the possible therapeutic strategies to follow in the context of advanced colorectal cancer and lung cancer.