The Loss of Spy1 Alters the Composition of Immune Cells and Expression of Immune Checkpoint Proteins

Triple Negative Breast Cancer (TNBC) is the most aggressive and heterogeneous subtype of breast cancer, comprising 15–20% of all cases. TNBC is defined by absence of estrogen, progesterone, and HER2 receptors, leaving patients with limited treatment options and poor prognoses. TNBC tumors contain a high population of cancer stem cells (CSCs), which possess enhanced self-renewal, metastatic potential, and resistance to therapies. CSCs contribute to immune evasion through the upregulation of immune checkpoint proteins (ICPs), which inhibit anti-tumor immune responses and create an immunosuppressive environment that promotes tumor survival. The cell cycle has been implicated in the regulation of ICP expression with CDK inhibition leading to increased ICP expression which, in combination with ICP inhibitors, leads to increased patient prognosis. Spy1 is an atypical activator of CDKs which is able to bypass traditional regulatory pathways, promoting proliferation, expanding CSC populations and increasing treatment resistance. Given the unique mechanism of Spy1 mediated CDK activation, it presents the opportunity it may regulate ICP expression, enhancing CSC-mediated immune evasion in TNBC. Understanding the role of Spy1 in this process could reveal novel therapeutic strategies to disrupt the immunosuppressive environment and improve the efficacy of immune checkpoint inhibitors, potentially transforming TNBC treatment outcomes.