Interleukin-1β (IL1), a pleiotropic cytokine, is involved in sleep regulation, tumor ontogeny, and immune responses. IL1 receptor adaptor proteins, including the IL1 receptor accessory protein (AcP), and its neuron-specific isoform, AcPb, are required for IL1 signaling. The AcPb isoform is resultant from alternate splicing of the AcP transcript. Our previous studies using AcPb null (AcPb-/-) mice characterized its participation in sleep regulation and emergent neuronal/glial network properties. Here, we investigated the impact of acute sleep disruption (SD) on brain cancer-related pathways in wild-type (WT) and AcPb-/- mice, employing RNA sequencing methods. In WT mice, SD increased AcPb mRNA levels, but not AcP mRNA, confirming prior similar work in rats. Transcriptome and pathway enrichment analyses demonstrated significant alterations in cancer, immune, and viral disease-related pathways in WT mice after SD, which were attenuated in AcPb-/- mice including multiple upregulated Src phosphorylation-signaling-dependent genes associated with cancer progression and metastasis. Our RNAseq findings, were analyzed within the context of The Cancer Genome Atlas Program (TCGA) data base; revealing an upregulation of sleep- and cancer-linked genes (e.g., IL-17B, IL-17RA, LCN2) across various tumors, including brain tumors, compared to normal tissues. Sleep-linked factors, identified through TCGA analyses, significantly impact patient prognosis and survival, particularly in low-grade glioma (LGG) and glioblastoma multiforme (GBM) patients. Overall, our findings suggest that SD promotes a pro-tumor environment through AcPb-modulated pathways.