De Martino, Ilaria (2025) Macrophage engineering with genetic circuits to promote anti-tumor immune response. [Tesi di dottorato]

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Abstract

The tumor microenvironment (TME) is a complex and dynamic system that plays a pivotal role in cancer progression, immune evasion, and therapeutic resistance. Among the various components of the TME, tumor-associated macrophages (TAMs) are particularly influential due to their ability to transition between the pro-inflammatory, antitumorigenic M1 phenotype, and the immunosuppressive, pro-tumorigenic M2 phenotype. This plasticity makes TAMs key players in promoting tumor growth and dampening immune responses. The First, therapeutic strategies aimed at targeting TAMs have focused on their depletion from the TME, but these approaches often lack precision and fail to harness the full potential of macrophages in cancer therapy adequately. In contrast, synthetic biology offers the possibility to precisely control cellular behaviour, enabling the development of therapies that dynamically respond to the TME. During my PhD project, I investigated strategies to reprogram macrophages as microprocessor. Specifically, I developed potential therapeutic output (actuators) to programme macrophage function that can be coupled to sensing modules, which allow spatio-temporal control of their production. I focused on two actuators aiming at i) enhancing phagocytic activity of macrophages and ii) skewing macrophage polarization towards an M1 phenotype by expressing the CV1 and Bacterial Compound (BC) respectively. CV1 blocks the don’t eat me axis based on the interaction of SIRP-CD47. BC is a bacterial component that once bound to the toll-like receptor triggers a repolarization mechanism from M2 phenotype to M1 triggering an anti-inflammatory response. Our data suggest that this approach can help the reprogramming of TAMs, effectively converting them into potent antitumor agents while maintaining tight control over their activity. Importantly a sensing-actuating system like ours, while enhancing the immune responses, mitigates the challenges posed by the uncontrolled nature of traditional therapies. By reshaping the immunosuppressive TME, this strategy paves the way for the development of more advanced and effective cancer immunotherapies, underscoring the transformative potential of engineered macrophages in oncology.

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