AbstractBackgroundCancer‐related cognitive impairment (CRCI) is a frequent consequence in breast cancer survivors after chemotherapy and lowers their quality of life (QOL). Psychological distress is frequently experienced by breast cancer survivors. There are currently few studies investigating the role of psychological distress in the genesis of CRCI.MethodsIn total, 122 breast cancer survivors after standard chemotherapy within a year were recruited and assessed using the Psychological Distress Thermometer (DT). Sixty breast cancer survivors had non‐psychological distress (NPD group) and sixty‐two breast cancer survivors with psychological distress (PD group). The scores of the Mini‐Mental State Examination (MMSE), prospective and retrospective memory (PM and RM) Questionnaire (PRMQ), and Functional Assessment of Cancer Therapy‐General (FACT‐G) and the levels of cytokines including interleukin‐1 beta (IL‐1β), tumor necrosis factor‐alpha (TNF‐α), and interleukin‐4 (IL‐4) were compared between the two groups. Using PROCESS, we investigated whether psychological distress predicted cognitive function based on MMSE through IL‐1β, TNF‐α, and IL‐4.ResultsThe PD group had higher scores on RM, PM, and FACT‐G and lower scores on MMSE than the NPD group (t= −11.357,t= −10.720,t= −15.419,t= 10.162, respectively;p< 0.05). Meanwhile, a higher level of IL‐1β, TNF‐α, and IL‐4 was observed in the PD group than in the NPD group (t= −3.961,t= −3.396,t= −3.269, respectively;p< 0.05). The link between psychological distress and cognitive function as measured by the MMSE was also mediated by IL‐1β, TNF‐α, and IL‐4 (effect size: 26%, 25%, and 24%).ConclusionBreast cancer patients with psychological distress displayed poor cognitive function, poor memory, and inferior quality of life, which was accompanied by higher cytokine levels of IL‐1β, TNF‐α, and IL‐4. This study demonstrated IL‐1β, TNF‐α, and IL‐4 as potential pathways to CRCI in response to ongoing psychological distress, which provided evidence for the involvement of psychological distress in CRCI in breast cancer survivors.