Colorectal cancer accounts for around 10% of all cancer cases worldwide, with rectal cancer comprising over one third and showing a concerning rise in incidence among young adults (under 50 years old). Current rectal cancer chemotherapy regimens are based on 5-fluorouracil, but its systemic administration lacks tumor selectivity and fast body clearance. Moreover, radiationinduced fibrosis not only reduces patients’ quality of life but also hampers anti-tumoral immune cell infiltration, mainly CD8+ T cells, frequently associated with a favorable prognosis in rectal cancer patients. Therefore, to address these, we propose a novel triple-modal strategy combining a carcinoembryonic antigen-targeted solid lipid nanoparticle encapsulating 5-fluorouracil, galunisertib (TGF-β receptor I kinase inhibitor) to prevent or revert radiotherapy-induced fibrosis, and radiotherapy to promote CD8+ T cells recruitment. The combinatory therapy efficacy will be assessed using a novel 3D post-radiation rectal cancer model and in vivo with a novel orthotopic rectal cancer model.