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Background and Purpose Metabolic reprogramming “Warburg effect” and immune checkpoint signaling are immunosuppressive hallmarks of Triple-Negative Breast Cancer (TNBC) contributing to the limited clinical applicability of immunotherapy. Biomaterials arise as novel tools for immunomodulation of the tumor microenvironment (TME) that can be used alongside conventional immunotherapeutics. Chitosan and lecithin are examples of versatile biomaterials with interesting immunomodulatory properties. In this study, we aimed at investigation of the role of carefully designed hybrid nanoparticles (NPs) on common mediators of both PD-L1 expression and glycolytic metabolism. Materials and Methods Hybrid lecithin-chitosan NPs were prepared and characterized. Their intracellular concentration, localization and effect on the viability of MDA-MB-231 cells were assessed. Glycolytic metabolism was quantified by measuring glucose consumption, ATP generation, lactate production and extracellular acidification. Nitric oxide (NO) production was quantified using Greiss reagent. Gene expression of iNOS, PI3K, Akt, mTOR, HIF-1α and PD-L1 was quantified by reverse transcription and q-RT-PCR. Results Chitosan, lecithin and the NPs-formulated forms have been shown to influence the “Warburg effect” and immune checkpoint signaling of TNBC cells differently. The composition of the hybrid systems dictated their subcellular localization and hence the positive or negative impact on the immunosuppressive characteristics of TNBC cells. Conclusions Carefully engineered hybrid lecithin-chitosan NPs could convert the immune-suppressive microenvironment of TNBC to an immune-active microenvironment via reduction of PD-L1 expression and reversal of the Warburg effect.

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