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Solid tumors generally exhibit chromosome copy number variation, which is typically caused by chromosomal instability (CIN) in mitosis. The resulting aneuploidy can drive evolution and associates with poor prognosis in various cancer types as well as poor response to T-cell checkpoint blockade in melanoma. Macrophages and the SIRPα-CD47 checkpoint are understudied in such contexts. Here, CIN is induced in poorly immunogenic B16F10 mouse melanoma cells using spindle assembly checkpoint MPS1 inhibitors that generate persistent micronuclei and diverse aneuploidy while skewing macrophages toward a tumoricidal 'M1-like' phenotype based on markers and short-term anti-tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels succumb similar to controls, but long-term survival is maximized by SIRPα blockade on adoptively transferred myeloid cells plus anti-tumor monoclonal IgG. Such cells are the initiating effector cells, and survivors make de novo anti-cancer IgG that not only promote phagocytosis of CD47-null cells but also suppress tumor growth. CIN does not affect the IgG response, but pairing CIN with maximal macrophage anti-cancer activity increases durable cures that possess a vaccination-like response against recurrence., Competing Interests: BH, MW, HZ, SP, LD, JA, AC, MT, NO, TM, DD No competing interests declared, (© 2023, Hayes et al.)

Immunotherapies against some solid tumour types have recently shown unprecedented, durable cures in the clinic, and the most successful thus far involves blocking inhibitory receptor 'checkpoints' on T cells. A similar approach with macrophages is emerging by blocking the ubiquitously expressed 'marker of self' CD47 from binding the inhibitory receptor SIRPα on macrophages. Here, we first summarize available information on the safety and efficacy of CD47 blockade, which raises some safety concerns with the clearance of 'self' cells but also suggests some success against haematological (liquid) and solid cancers. Checkpoint blockade generally benefits from parallel activation of the immune cell, which can occur for macrophages in multiple ways, such as by combination with a second, tumour-opsonizing antibody and perhaps also via rigidity sensing. Cytoskeletal forces in phagocytosis and inhibitory 'self'-signalling are thus reviewed together with macrophage mechanosensing, which extends to regulating levels of SIRPα and the nuclear protein lamin A, which affects phenotype and cell trafficking. Considerations of such physical factors in cancer and the immune system can inform the design of new immunotherapies and help to refine existing therapies to improve safety and efficacy. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.