Figure 7: Schematic representation outlining the role of how modulating the TK/ShcA axis impacts breast cancer immune suppression.

Elevated STAT3 signalling promotes immune suppression in ShcA-WT breast tumours, which suppresses STAT1-driven anti-tumorigenic immune responses. Instead, STAT1 further contributes to immune evasion by increasing PD-L1 levels in mammary tumours. As such, these tumours display a modest sensitivity to PD1 immune checkpoint blockade or tumour vaccination strategies. In contrast, loss of the phospho-pY239/240 ShcA signalling (Shc2F) significantly and specifically impairs STAT3 activation in breast cancer cells. This relieves STAT3-driven immune suppression, leading to stromally induced activation of STAT1-mediated anti-tumorigenic responses in mammary tumours, which together promote immune surveillance and significant responsiveness to anti-PD1 therapies or tumour vaccines. Finally, specific loss of pY-313 ShcA signalling (313F) directly increases STAT1 signalling in breast cancer cells, leading to a compensatory hyperactivation of STAT3 signalling. Heightened STAT3 signalling in 313F mammary tumours sustains immune evasion, leading to increased resistance to PD1 checkpoint inhibitors. Paradoxically, however, increased STAT1 signalling in these tumours increases their sensitivity to tumour vaccination strategies, owing to the heightened increase in baseline STAT1 signalling.