Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance

Simple Summary In the last decades, identification of the factors/mechanisms leading to cancer development has advanced the way clinicians combat this pathology. Indeed, the use of adjuvant chemotherapies and targeted therapies has markedly contributed to prolonging the survival of cancer patients. Unfortunately, however, many cancer patients experience primary or acquired resistance to these therapies, and this has been linked to various factors, including the presence of a tumor microenvironment that restrains the anti-tumor immunity. In this article, we describe the ability of interleukin-34, a protein produced in excess in many cancers, to modulate the function of various immune cells, with the downstream effect of generating a tumor microenvironment that sustains cancer cell growth and, at the same time, enhances the resistance of cancers against chemotherapy and immunotherapy. Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel effective therapeutic compounds. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are major components of the suppressive tumor microenvironment and are critical drivers of immunosuppression, creating a tumor-promoting and drug-resistant niche. In this regard, therapeutic strategies to tackle immunosuppressive cells are an interesting option to increase anti-tumor immune responses and overcome the occurrence of drug resistance. Accumulating evidence indicates that interleukin-34 (IL-34), a cytokine produced by cancer cells, and/or TAMs act as a linker between induction of a tumor-associated immunosuppressive microenvironment and drug resistance. In this article, we review the current data supporting the role of IL-34 in the differentiation/function of immune suppressive cells and, hence, in the mechanisms leading to therapeutic resistance in various cancers.