Exploiting neutrophils-lipid interactions to design novel strategies to target neutrophils in cancer

People involved

tba

Abstract

Phospholipids are fundamental structural components of cellular membranes and serve as potent regulators of immune recognition, leukocyte activation, and inflammatory resolution.1) The ability of phospholipids to interact selectively with different immune cells such as macrophages.2) In cancer, neutrophils, particularly N2-like tumor-associated neutrophils (TANs), play diverse roles in tumor progression, metastasis, and therapeutic resistance. Reprogramming these cells toward an anti-tumoral, N1-like phenotype represents an emerging therapeutic strategy.3)

In this project, we will explore novel receptor-phospholipid interactions to identify phospholipids capable of selectively targeting neutrophil subsets. We hypothesize that incorporation of these phospholipids into liposomal membranes can be exploited as targeting moieties to direct liposomes toward defined neutrophil subpopulations. We will prepare and characterize liposomes for their physicochemical properties, stability, and binding to and uptake by human neutrophil subsets. Promising formulations will then be evaluated in vivo for biodistribution, tumor homing, and cellular distribution using advanced imaging modalities in mouse tumor models. Finally, we will assess the therapeutic efficacy of drug-loaded TAN-targeted liposomes in both immunoreactive and immunosuppressive tumor models by focusing on neutrophil modulation from an N2-like to N1-like phenotype.

Overall, this project aims to establish a new neutrophil-targeted liposomal platform based on phospholipid-receptor interaction, enabling specific modulation of TANs and providing a novel immunotherapeutic platform to enhance anti-tumor effects. Furthermore, the phospholipid research community will benefit from new mechanistic insights of using phospholipids as targeting ligands, which will broaden the translational relevance of phospholipids.

Benefit for the community

This project advances the phospholipid research field by defining how specific phospholipid compositions influence liposome recognition, binding, and uptake by neutrophils, particularly tumor-associated neutrophils in the cancer microenvironment. Although phospholipids are widely used in liposomal formulations, their potential as selective targeting ligands remains underexplored. By systematically comparing phospholipid-receptor interactions and identifying motifs that guide liposomes to distinct neutrophil subsets, this work expands phospholipid science beyond structural and biophysical roles toward immune-targeted drug delivery.

The project addresses an important unmet need in cancer therapy: the limited clinical success of current immunotherapies in solid tumors. By developing phospholipid-based ligands that direct liposomes to neutrophils and modulate their phenotype, this project offers a new route to overcome limitation to immunotherapy.

The phospholipid research community will benefit from new mechanistic insights, design rules, and validated phospholipid structures that enable immune-cell-selective targeting. These outcomes will broaden the translational relevance of phospholipids and stimulate their use in future immune-therapeutics.

Visit the supervisors lab

Contact to Jai Prakash.