Targeting Toll-Like Receptors for the Treatment of Lung Cancer

Lung cancer (LC) remains a significant concern for the community, causing the greatest number of fatalities linked to cancer globally. Toll-like receptors (TLRs) are widely found in immune-related cells including plasmacytoid dendritic cells, monocytes, and B lymphocytes, as well as in lower concentrations throughout human pulmonary and epithelial cells. Newer investigations have displayed the crucial role of TLRs in activating innate immunity. Therefore, stimulating the immune system externally through TLRs may offer a potential approach to combat cancer. However, this immune system activation could also contribute to underlying chronic inflammation, ultimately promoting the progression of pulmonary carcinoma. Cancerous cells possess distinct characteristics, including their ability to multiply indefinitely and resist programmed cell death (apoptosis). TLRs are highly active in most native lung cells and infiltrating lymphocytes with myeloid and lymphoid origins. Notably, TLRs 1, 2, 3, 4, 5, 6, and 9 are prominently expressed in pulmonary epithelial cells. TLRs may enhance LC cell proliferation by transmitting signals that promote cell growth or prevent apoptosis. Surprisingly, LC cells exhibit higher levels of TLR2, TLR4, TLR7/TLR8, and TLR9 expression compared to “normal” lung cells. TLR4 and TLR9, in particular, are well-known TLRs associated with the development of LC. TLR4 activation has been demonstrated to enhance the growth of the human lung adenocarcinoma cell line A549 in a time- and dose-related approach upon stimulation with the TLR4 ligand LPS. This chapter delves into potential pathways through which TLR ligands could potentially facilitate the development and/or spread of LC. Overall, understanding the complex interplay between TLRs and LC is crucial for devising strategies to leverage these receptors for therapeutic purposes while mitigating the negative consequences of chronic inflammation.