Blood and saliva provide complementary but non-redundant host transcriptomic responses to cancer

Blood and saliva are two of the most accessible biofluids for non-invasive molecular profiling, yet it remains unclear whether they report the same biological response to cancer. Using matched whole-blood and saliva transcriptomic profiling from patients with multiple malignancies (27 samples from six cancers [prostate, lung, breast, pancreatic, colon, or melanoma]) and 9 healthy controls, we evaluated the extent to which these compartments share or diverge in their cancer-associated responses. Although the majority of expressed genes were shared between blood and saliva (about 25,400 detected in blood and 24,100 in saliva, with 86% of salivary genes detectable in blood), global transcriptomic analyses demonstrated that biofluid identity was the dominant source of variation. Cancer-associated transcriptional changes exhibited weak cross-biofluid concordance ( r = 0.01–0.28), which may indicate that the two compartments respond to malignancy through distinct biological mechanisms. Blood-derived signatures were enriched for systemic immune, inflammatory, hematopoietic, and host-defense pathways, whereas salivary signatures emphasized epithelial, secretory, metabolic, and microbial-associated processes. Saliva additionally contained a rich microbial transcriptome absent from blood. These findings demonstrate that blood and saliva provide complementary rather than interchangeable information regarding host responses to cancer and support integrated multi-biofluid approaches for future cancer detection and disease monitoring. Because the cohort is small and heterogeneous, with only three to seven patients per malignancy, all per-cancer findings are exploratory and hypothesis-generating rather than generalizable; the principal conclusion concerns the global relationship between the two biofluids.