<p>Monocytes and macrophages are versatile immune sentinels that are present in nearly all tissues, where they continually adapt to local cues. In cancer, their functions are context-dependent — often linked to tumour growth and poor prognosis but also capable of driving potent antitumour immunity. To explain this dichotomy, we frame cancer cells as ‘infectious self’, having both pathogen-like and self-like features. In turn, monocytes and macrophages adopt modular programmes across primary and metastatic tumour sites — as well as along haematogenous, lymphatic and transcoelomic routes of dissemination — that are shaped by oncogenic lesions, cancer cell differentiation states, tissue perturbations and organism-level variables. These cells are promising yet challenging therapeutic targets. Opportunities include blocking the recruitment, differentiation and scavenging activity of pro-tumour monocytes and macrophages; activating pattern recognition receptor signalling pathways and lymphocyte help; inducing cancer cell phagocytosis; and rewiring key intracellular signalling nodes. Emerging cellular and gene-based approaches — such as chimeric receptor engineering and in vivo target delivery — further expand this toolkit and underscore the potential to reprogramme monocyte and macrophage responses for durable control of solid tumours.</p>