Natural killer (NK) cells are central to immune surveillance, yet their mechanisms of activation in anti-tumour immunity remain incompletely understood. The activating receptor NKp44, encoded by NCR2, has emerged as a key player in anti-tumour responses through its recognition of platelet-derived growth factor D (PDGF-DD), a tumour-secreted factor traditionally associated with tumour cell proliferation and angiogenesis. NKp44 binding to PDGF-DD triggers IFN-γ and TNF secretion, inducing tumour growth arrest and correlating with improved survival in glioblastoma.

Beyond direct cytotoxicity, NKp44 cooperates with other innate immune receptors to amplify anti-tumour responses. In plasmacytoid dendritic cells (PDCs), NKp44 engagement with PDGF-DD enhances TLR9-driven IFN-α, TNF, and IL-6 production, revealing a broader role in modulating innate immunity. Additionally, NKp44+ NK cell function is enhanced in mouse models by blocking the murine inhibitory receptor CD96 or through CpG-oligonucleotide activation of TLR9, reinforcing the notion that NKp44 signalling integrates multiple innate immune pathways to shape anti-tumour responses.

These findings highlight NKp44 as a dynamic hub of innate immune coordination, linking NK cells, PDCs, and other immune subsets in the tumour microenvironment. However, the dual role of PDGF-DD in both tumour progression and immune activation presents a challenge for therapeutic targeting. Understanding the complex interplay between NKp44 and other innate immune receptors will be essential for optimising NK cell-based immunotherapies, particularly in solid tumours where NK cell efficacy has been limited.

Our work positions NKp44 as a promising immunotherapeutic target, offering new strategies to enhance innate immune activation and improve patient outcomes for tumours expressing PDGF-DD.