Novel targeting strategies to reprogram cancer-associated fibroblasts in the tumor microenvironment

The tumor microenvironment (TME) is a critical driver of cancer progression, metastasis, and therapeutic resistance. Among its various cellular components, cancer associated fibroblasts (CAFs) are particularly essential due to their ability to remodel the extracellular matrix (ECM), secrete growth factors and cytokines, and interact with other cell types to promote tumorigenesis. The heterogeneity of CAFs, increasingly recognized as subtypes including myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs), adds complexity to their role in cancer biology. This diversity also complicates the therapeutic potential, yet targeting CAFs has emerged as a promising strategy to overcome the therapeutic resistance associated with the TME. However, the development of effective therapies is challenging due to the complex interactions between CAF subtypes, immune cells, and tumor cells. This dissertation addresses these challenges by exploring innovative approaches to selectively target different CAF subtypes, aiming to disrupt their pro-tumorigenic functions and improve the efficacy of chemotherapy. The first part of this dissertation discusses the biology of CAFs as well as potential therapeutic strategies. Special attention is given to pancreatic ductal adenocarcinoma (PDAC), one of the most desmoplastic tumors, underscoring the importance of developing biologically relevant models that reflect the TME complexity. The second part of this dissertation introduces a polymeric nanofiber system designed for the controlled co-delivery of a p21-activated kinase 1 inhibitor, FRAX597, and the chemotherapeutic agent paclitaxel. This system was tested in stroma-rich breast cancer models highlighting the potential of targeting CAFs to overcome chemoresistance in solid tumors. In the third part, integrins α5 and α11 were identified as potential drug delivery targets for iCAFs/myCAFs and myCAFs only, respectively. Utilizing novel peptides AV3 and AXI, surface-functionalized polymeric nanoparticles showed selective targeting and enhanced PDAC biodistribution. Building on this, the fourth part investigates the therapeutic efficacy of these nanoparticles in delivering a monoacylglycerol lipase inhibitor, URB602 and an aryl hydrocarbon receptor agonist, YL109 to CAF subtypes, resulting in TME modulation in preclinical KPC model. Finally, the fifth part explores the potential of specific targets inhibition within CAFs, including fibroblast growth factor receptor-4 and dipeptidyl peptidase-4, demonstrating therapeutic suppression of iCAFs, myCAFs and significant modulation of PDAC TME.