Increasing evidence shows that microbial secretions are able to modulate local immune responses in epithelial cells and thus play a key role in inflammatory disease, tumour development and cancer progression. Premalignant actinic keratosis (AK) and squamous cell carcinoma (SCC) skin lesions have been associated with the presence of specific Staphylococci subspecies, however, the cause-effect relationship remains unclear. We hypothesise that bacterial products from lesion-associated Staphylococci strains induce inflammatory and metabolic stress in keratinocytes and thus may contribute to disease progression from AK to SCC. The current study therefore investigates the impact of the secretomes of Staphylococcus isolates commonly found on sun-damaged skin on keratinocyte cell metabolism and cytokine production in vitro. Bacterial isolates from clinical control and lesional skin swabs were cultured in growth medium and the corresponding supernatants co-incubated with different keratinocyte cell lines. Most Staphylococcal supernatants were strong inducers of interleukin-6 in HaCaT and primary AK keratinocytes whereas others dampened cytokine release. Those Staphylococcal secretomes identified as less immunostimulatory were found to depress mitochondrial metabolism considerably. These findings suggest that bioactive products secreted by microbes can promote metabolic and inflammatory processes in the skin which have been linked to carcinogenesis. Future experiments will aim to identify the bioactive bacterial compounds and their molecular pathways via RNAseq and mass spectrometry approaches.