Improving Treatment Selection and Overcoming Resistance in Colorectal Cancer: From Predictive Biomarkers to Novel Therapeutic Ta

Despite major advances in the molecular characterization and treatment of colorectal cancer (CRC), therapeutic resistance and disease progression remain major challenges, particularly in the metastatic setting. The marked biological heterogeneity of CRC translates into heterogeneous treatment responses, highlighting several unmet needs: identifying biomarkers to better select patients for existing therapies, discovering novel therapeutic vulnerabilities, understanding mechanisms that shape an immunosuppressive tumor microenvironment, and identifying molecular drivers of metastatic progression.

Our research addresses these challenges through complementary translational approaches. We investigate biomarkers of response to standard chemotherapy, explore novel therapeutic targets such as PARG, study the contribution of the CD73–adenosine axis to the immunosuppressive microenvironment of KRAS-mutant CRC, and investigate whether targeted degradation of CDK5 can interfere with metastatic progression. Together, these projects share a common objective: to translate the biological understanding of treatment response and tumor progression into more effective therapeutic strategies.

As an example of this approach, I will focus on our work investigating chemokines as modulators and biomarkers of response to oxaliplatin-based chemotherapy. Starting from experimental models of oxaliplatin resistance, we identified profound alterations in chemokine signaling and subsequently explored their clinical relevance in patients with metastatic CRC. These studies identified CXCL13 as a particularly interesting candidate, linking circulating chemokine dynamics with clinical outcome, tumor immunogenicity and tertiary lymphoid structure (TLS)-related signatures.

Our current work aims to understand the biological basis of this association by characterizing TLS formation and maturation in colorectal cancer liver metastases and determining whether oxaliplatin-induced immunogenic cell death contributes to their development. We are also investigating whether this immune remodeling is specific to oxaliplatin or extends to other chemotherapy regimens.

Overall, our work illustrates how integrating mechanistic, preclinical and patient-based studies can help identify predictive biomarkers, uncover novel therapeutic vulnerabilities and provide new strategies to limit disease progression in colorectal cancer.