Enhancing natural killer cell anti-tumour activity through macrophage manipulation

Abstract

The tumour microenvironment (TME) is a complex and dynamic environment containing diverse cellular, stromal and soluble factors, that collectively influence cancer progression, immune evasion and therapeutic resistance. Among the immune components of the TME, macrophages and natural killer (NK) cells are key players, whose interactions, particularly their crosstalk, critically shape anti-tumour immunity. The macrophage-NK cell interplay can either promote or suppress immune responses depending on the context, representing both a challenge and a therapeutic opportunity. NK cells are key effectors capable of recognising and eliminating malignant cells without prior sensitisation, whereas macrophages exhibit remarkable plasticity, functioning as either promoters or suppressors of tumour immunity depending on their activation state. This review focuses on current strategies to harness macrophages in cancer therapy, including phenotype repolarisation, selective depletion, and disruption or enhancement of the macrophage-NK cell crosstalk to enhance NK cell-mediated tumour surveillance. Finally, we highlight emerging technologies, such as single-cell RNA sequencing, spatial transcriptomics, and proteomics, as powerful tools to elucidate the dynamic interplay between macrophages and NK cells and inform the next generation of immunotherapeutic interventions.

Keywords: cancer; immune crosstalk; immunotherapy; macrophages; natural killer cells.

Figure 1

Polarised TAM-NK cell interactions in the TME. TAMs modulate NK cell activity depending on their polarisation state. Pro-inflammatory TAMs (left) promote anti-tumour responses by secreting IL-12, IL-15, IL-18, and TNF-α, and enhancing NK cell activation and IFN-γ production through engagement of activating receptors (e.g., NKG2D, NKp80, LFA-1). In contrast, anti-inflammatory TAMs (right) facilitate immune suppression via IL-10 and TGF-β, and upregulating inhibitory ligands (e.g., PD-L1, HLA-E, NKG2DL) that engage inhibitory NK cell receptors (e.g., PD-1, NKG2A, KIRs). This bidirectional crosstalk shapes the tumour microenvironment by either enhancing or suppressing NK cell cytotoxicity.

Figure 2

Strategies for TAM repolarisation in the TME. There are various approaches to reprogramme TAMs from an anti-inflammatory, pro-tumour phenotype to a pro-inflammatory, anti-tumour state. Therapeutic strategies include activation of pro-inflammatory-inducing pathways via agents targeting Toll-like receptors (TLRs), and immune checkpoint blockade (e.g., anti-PD-1/PD-L1) to relieve TAM-mediated immunosuppression. The reprogrammed TAMs exhibit enhanced phagocytic activity, antigen presentation, and pro-inflammatory cytokine secretion, contributing to improved anti-tumour immunity.

Figure 3

Therapeutic strategies to reduce TAM accumulation in the TME. Approaches to target TAM recruitment and survival to limit their accumulation in the TME include: inhibition of the colony-stimulating factor 1 receptor (CSF1R) pathway (through genetic knockout (CSF1R KO) or pharmacological inhibition using CSF1R inhibitor BLZ945) (top); disruption of the CCL2-CCR2 axis using anti-CCL2 antibodies or CCR2 antagonists (centre); chimeric antigen receptor (CAR)-T cells engineered to recognise the TAM marker folate receptor β (FRβ) (bottom). Collectively, these strategies contribute to reduced TAM accumulation in the TME, potentially enhancing anti-tumour immunity.

Figure 4

Modulating TAM–NK cell crosstalk to influence anti-tumour immunity. Strategies to either enhance or disrupt the interaction between TAMs and NK cells in the TME aim to restore or enhance NK cell cytotoxicity and contribute to anti-tumour responses. On the left, enhancing crosstalk is achieved through TLR agonists and CSFR1 stimulation, which upregulate NKG2D ligands (NKG2DL) on TAMs and promote NK cell activation. Inhibition of Gas6-AXL signalling using anti-Gas6 antibodies further supports immune activation. On the right, disruption of immunosuppressive crosstalk is demonstrated via blockade of TGF-β signalling (using anti-TGF-β antibodies) and interference with inhibitory CD48-2B4 interactions (via anti-2B4 antibodies). Additionally, recombinant NKG2DL can be used to inhibit NKG2D-mediated suppression.

Figure 5

Spatial transcriptomic insights into TAM-NK cell crosstalk in the TME. Recent spatial transcriptomic analyses reveal altered distributions of TAMs and NK cells across tumour regions. Left: Anti-inflammatory macrophage-rich niches predominate in the TME of both adenocarcinoma and squamous cell carcinoma, with a corresponding reduction in NK cell infiltration and cytotoxic gene expression. Based on work by De Zuani et al. (226). Middle: In non-small cell lung cancer, TREM2⁺ TAMs are enriched within the tumour core, acting as a barrier to NK cell infiltration and promoting an immunosuppressive landscape. Right: Therapeutic blockade of TREM2 reverses this exclusion, enhancing NK cell activation. Middle and right panels based on findings from Park et al. (227).