Our group recently showed that cationic amphiphilic drugs (CADs) can complex nucleic acids in lipid nanoparticles (LNPs) for drug combination therapy. This project aims to evaluate this CAD-LNP platform in cancer immunotherapy. Immune checkpoint blockade (ICB), e.g. via PD-L1 antibodies, has demonstrated clinical efficacy, but is hampered by immune-related off-target effects following systemic exposure and low response rates due to an immunosuppressive tumor microenvironment (TME). Antihistamine CADs can create a more pro-inflammatory TME by promoting recruitment of tumor-reactive T cells and reversing ICB resistance, as well as inducing lysosomal cancer cell death (LCD). However, antihistamine monotherapy leads to insufficient anti-tumor responses and could likewise benefit from a more targeted approach to improve its therapeutic index. LNPs offer great potential for drug targeting to the TME. Opposed to the systemic administration of high dose CADs and ICB antibody in solution, we propose to co-encapsulate antihistamines and ICB small interfering RNAs (siRNAs) into a single CAD-LNP formulation to target and reprogram the TME. Hereto, we first aim to screen antihistamine CADs for their anti-tumor and immune-modulating effects. Potent CADs will be co-formulated with PD-L1 siRNA into CAD-LNPs to enable co-delivery to distinct tumor associated cells. Finall, therapeutic proof-of-concept will be sought in a syngeneic orthotopic mouse model of triple negative breast cancer.