Parkinson’s disease (PD) is defined by the progressive accumulation of misfolded α-synuclein (αSyn) across the gut–brain axis, yet the cellular systems that normally contain this burden are only beginning to be understood. Among them, tissue-resident macrophages (RTM) occupy strategically positioned niches and functionally interact with their microenvironment. In this Perspective, we examine how muscularis externa macrophages in the enteric nervous system, parenchymal microglia, and border-associated macrophages in the central nervous system respond to αSyn and shape disease progression. We argue that these RTM serve as early sentinels of synucleinopathy by taking up extracellular αSyn and attempting to degrade it through lysosomal pathways. However, with ageing and in the context of genetic or environmental stress, this protective function may break down. As degradative capacity declines, RTM may enter dysfunctional states marked by cellular stress, incomplete processing of αSyn, propagation of pathogenic species, and enhanced antigen presentation. In this way, RTM may influence not only the local handling of αSyn, but also the emergence of adaptive immune responses and neuroinflammation across the enteric nervous system (ENS)–central nervous system (CNS) axis. We further discuss how anatomical niche, ontogeny, and αSyn conformational diversity may shape these responses, and how restoring macrophage proteostatic function could offer therapeutic opportunities to limit disease progression.

Multiple clinical and translational studies have shown that infiltration of tumour-associated neutrophils is associated with advanced disease stages, increased metastatic spread, therapeutic resistance, and poorer overall survival across various cancer types. Beyond their traditional role as first responders to tissue damage and pathogen infection, neutrophils within the tumour microenvironment (TME) display remarkable functional plasticity, adopting phenotypes that can promote angiogenesis, extracellular matrix remodelling, immune suppression, and tumour cell invasion. Importantly, it is now recognised that the prognostic impact of neutrophils is highly context-dependent, shaped by tumour type, stage, and the evolving inflammatory milieu. Intravital imaging studies have revealed dynamic neutrophil behaviours, including distinct migratory patterns between intra-tumoural and peri-tumoural regions, interactions with tumour and immune cells, and contributions to processes such as metastasis and immune suppression. However, there is a lack of understanding of how transcriptionally defined neutrophil subsets translate into specific functional and behavioural states in the TME in vivo. This mini-review spotlights intravital imaging approaches that illuminate neutrophil dynamics in tumours. We also discuss how extrinsic regulators, including cancer-associated fibroblasts and neural inputs, direct neutrophil dynamics, further contributing to TME complexity.