Circadian rhythm (CR) governs systemic and tissue physiological homeostasis by regulating sleep-wake cycles, hormone secretion, and metabolism. CR disruption (CRD), such as shift work, has been associated with increased cancer risk, particularly female breast cancer (BC), yet the mechanisms underlying breast tumorigenesis and immunosuppression resulting from a specific clock gene dysfunction remain unclear. Here, we identify that circadian regulator Period 2 (PER2) is significantly downregulated in BC and correlates with poor prognosis. PER2 functional deficiency mice ( PAS-B domain deletion, Per2 ^m/m ) display high susceptibility to DMBA/MPA-induced breast tumors. Tumor microenvironment (TME) profiling reveals that compared with Per2 ^wt tumors induced in Per2 ^wt mice, Per2 ^m/m tumors generated in Per2 ^m/m mice show reduced CD8⁺ T cells and M1-like macrophages infiltration and increased Foxp3 ⁺ Tregs and M2-like macrophages. Of note, reciprocal transplantation of Per2 ^m/m and Per2 ^wt tumors into Per2 ^wt or Per2 ^m/m mouse hosts reveals that systemic PER2 functional deficiency status not only boosts tumor growth but also promotes immunosuppression in TME. Consistently, Per2 knockdown in tumor cells enhances tumor cell proliferation and immune evasion in WT hosts. Mechanistically, PER2 knockdown leads to aberrant CLOCK transactivation, which upregulates the co-expression of HER2 and CD47, thereby leading to tumor aggressive growth with limited macrophage immune checkpoint surveillance. Collectively, our findings suggest that PER2 functional deficiency-driven CLOCK-HER2/CD47 axis promotes BC susceptibility and tumor immunosuppression, which provides a potential therapeutic target to mitigate CRD-associated BC risk and aggressiveness.

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