The myeloid SRC family kinase HCK regulates breast cancer growth by activating tumor associated macrophage-led invasion and inhibiting cytotoxic T cell activity

Regarding immune evasion, HCK-deficient tumors contained increased CD8+ T cell numbers and, while CD8+ T cell depletion reduced survival in all mouse cohorts, CD8+ T cell-depleted HCK-deficient mice survived much longer than CD8+ T cell-replete control mice. Characterisation of the tumour microenvironment by single cell sequencing showed 5 major subtypes of TAMs (immunoregulatory (Folr2high ), inflammatory (MHC-IIhigh ), interferon-primed, angiogenic and tissue resident), which together made up 40% of cells in the tumour.

While Hck activity did not affect the recruitment of TAMs or their subtype composition, pathway analysis showed that its loss decreased TAM motility and increased their interferon signalling and reduced EMT pathways in the Py8119 tumor cells. This study provides evidence that HCK activity in TAMs enhances tumour growth via promotion of invasive behaviour as well as suppression of anti-tumor immunity. These findings highlight HCK as a promising therapeutic target to limit tumor progression.