Inflammatory Networks in Renal Cell Carcinoma

Abstract

Cancer-associated inflammation has been established as a hallmark feature of almost all solid cancers. Tumor-extrinsic and intrinsic signaling pathways regulate the process of cancer-associated inflammation. Tumor-extrinsic inflammation is triggered by many factors, including infection, obesity, autoimmune disorders, and exposure to toxic and radioactive substances. Intrinsic inflammation can be induced by genomic mutation, genome instability and epigenetic remodeling in cancer cells that promote immunosuppressive traits, inducing the recruitment and activation of inflammatory immune cells. In RCC, many cancer cell-intrinsic alterations are assembled, upregulating inflammatory pathways, which enhance chemokine release and neoantigen expression. Furthermore, immune cells activate the endothelium and induce metabolic shifts, thereby amplifying both the paracrine and autocrine inflammatory loops to promote RCC tumor growth and progression. Together with tumor-extrinsic inflammatory factors, tumor-intrinsic signaling pathways trigger a Janus-faced tumor microenvironment, thereby simultaneously promoting or inhibiting tumor growth. For therapeutic success, it is important to understand the pathomechanisms of cancer-associated inflammation, which promote cancer progression. In this review, we describe the molecular mechanisms of cancer-associated inflammation that influence cancer and immune cell functions, thereby increasing tumor malignancy and anti-cancer resistance. We also discuss the potential of anti-inflammatory treatments, which may provide clinical benefits in RCCs and possible avenues for therapy and future research.

Genomic and Transcriptomic Characteristics of Tumors of Patients with Metastatic Clear Cell Renal Cell Carcinoma Clinically Benefiting from First-Line Treatment with Ipilimumab Plus Nivolumab

“…Enhanced IL-6-JAK-STAT3 in conjunction with IFN ␣ and IFN ␥ signaling is known to impair cytotoxic T-cell activation resulting in a diminished response to ICIs in clear cell renal cell carcinoma [32]. Gene expression analyses have reported the overexpression of inflammatory and immunerelated signatures among patients who respond to immunotherapy or immunotherapy-containing regimens across different cancers [33][34][35].…”

Modifying the electrical, optical, and magnetic properties of cancer cells: A comprehensive approach for cancer management

“…This innovative nanoplatform not only demonstrated significant efficacy against tumors but also activated the innate immune system by activating NK cells via the cGAS-STING pathway [127]. This pathway is well known for its role in detecting cytoplasmic DNA and initiating immunological responses [128]. Thus, improving the therapeutic effect of radiation may be achieved by the strategic incorporation of metformin, an immunomodulatory medication that is often used to treat diabetes, into a MnO 2 -based…”

Immunotherapy of Clear-Cell Renal-Cell Carcinoma

“…Indeed, it has been shown that during the development of RCC, NF-kB pathways are implicated in abnormal inflammatory responses, thereby contributing to the progression of the disease. Loss of the von Hippel Lindau (VHL) tumor suppressor gene, a typical mutation found in most RCC patients that will be discussed below, seems to promote the pathological roles of NF-κB [ 29 ].…”

“…It has been demonstrated that, in ccRCC, this condition can induce the stabilization of hypoxia-inducible factors-αs (HIF1α and 2α), which in turn can promote metabolic reprogramming, angiogenesis, and epithelial–mesenchymal transition (EMT) associated with the downregulation of tight junction protein (occludin, claudin-1, and E-cadherin) expression and apical–basal polarity loss. The combination of these factors subsequently contributes to the growth and spread of the most common RCC subtype [ 29 , 63 , 65 ].…”

“…In this regard, in addition to the therapies already described, research has recently also focused on the development of a medicament aimed at the direct inhibition of HIF2α, named Belzutifan. This therapy is targeted towards adult patients with VHL-associated RCC, as well as those suffering from central nervous system hemangioblastomas or pancreatic neuroendocrine tumors, and has been approved by the Food and Drug Administration (FDA) [ 29 , 66 ].…”