SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19), has resulted in unprecedented morbidity and mortality in the world. Epidemiological and clinical data reported that symptoms can last up to four weeks after infection, or they can present four to 12 weeks after the acute phase of COVID-19, or the disease persists for a long time leading to long COVID (LC) [1]. LC is also associated with pre-existing pathologies, such as respiratory and cardiovascular diseases, advanced age, high body mass index, or previous history of comorbidities such as chronic kidney injury, and cancer [2]. In particular, growing clinical data have reported that renal function impairment represents a relevant complication requiring long follow-up by nephrologists ^[3][4][5][6][3,4,5,6].

The risk of developing a serious disease in cancer patients with COVID-19 is about 4 times higher compared to those without malignancy [7], because of compromised immune systems caused by tumor depletion, malnutrition, and anticancer treatments. In addition, SARS-CoV-2 can activate the metabolism of tumor cells, such as increasing glycolysis which in turn can facilitate virus replication ^[8][9][8,9] and alter the metabolic pathways of cancer cells, accelerating tumor progression [10]. In vitro studies performed by infecting the human colon cell line (Caco-2) with SARS-CoV-2 have demonstrated that the infection alters central cellular pathways, such as translation, splicing, carbon, nucleic and acid metabolism [11], blocking viral replication [12]. In addition, some authors have demonstrated that 24 h after SARS-CoV-2 infection, the proteomics of Caco-2 cells undergoes an extensive alteration, leading to a decrease in metabolic proteins rich in cholesterol and an increase in proteins that modify carbohydrate metabolism [11]. In this way, SARS-CoV-2 infection could reprogram metabolism in tumor cells to facilitate viral replication and influence tumor progression ^[13][14][13,14]. Epidemiological studies showed that COVID-19 infection does not affect the mortality rate among patients with early-stage cancer [15], whereas, patients with advanced cancer are not only more likely to be infected by SARS-CoV-2 but also have a worse prognosis, especially if male [16]. Most patients hospitalized for COVID-19, have acute kidney injury (AKI) and although the pathophysiology of AKI in these patients is not fully understood, the studies suggest that AKI, as well as chronic kidney disease, are associated with poor survival ^[5][17][5,17] and with an increased incidence of renal cancer [18]. The frequent renal involvement with organ damage in patients with COVID-19 is undoubtedly multifactorial, but the expression on renal cells of the key receptors promoting SARS-CoV-2 entry, such as ACE2, TMPRSS2, and NRP1 can make the kidney particularly susceptible to SARS-CoV-2 infection ^[19][20][21][19,20,21].

23. Expression of SARS-CoV-2 Entry Factors in Normal and Cancer Renal Cells

2.1. Angiotensin-Converting Enzyme 2 (ACE2)

3.1. Angiotensin-Converting Enzyme 2 (ACE2)

ACE2 is the primary receptor for SARS-CoV-2 ^[22][34]. It is known to be expressed in various tissues throughout the body, including the lungs, blood vessels, liver, and gastrointestinal tract, and at high levels in the kidneys and heart ^[23][35]. At the physiological level, ACE2 is involved in regulating blood pressure and plays a role in the renin-angiotensin-aldosterone system (RAS) where the overactivation of the RAS pathways results in hypertension, kidney damage, and cardiovascular disease, in addition to being one of the pivotal signaling in SARS-CoV-2–induced nephrotic syndrome ^[24][36]. ACE2 is a zinc metalloenzyme and carboxypeptidase expressed on the surface of endothelial cells and other cell types. Although its primary substrate is angiotensin type II, it can hydrolyze numerous other physiological substrates ^[24][36]. The enzymatic activity of ACE2 cleaves the C-terminal end of angiotensin II, producing the 7 amino acid peptide Ang(1–7). The binding of Ang(1–7) to the Mas receptor (MasR) antagonizes numerous effects of Ang II in a negative feedback loop mechanism ^[25][37]. At the cellular level, angiotensin II induces various signaling pathways, including serine/threonine kinase, ERK, JNK/MAPK, and PKC ^[26][38]. The activation of these pathways through G protein-coupled receptors induces downstream cytokines IL-6 (interleukin 6) and TNF-α (tumor necrosis factor-alpha) ^[27][28][39,40], important mediators of inflammatory processes and the antibody immune response. Of interest to COVID-19 disease, angiotensin II can increase inflammation and cell death in the lung alveoli resulting in a dramatic decrease in the amount of oxygen in the body ^[25][37]. These harmful effects of angiotensin II are reduced by the activity of ACE2, which works as a key protective enzyme by reducing inflammation, oxidative stress, and fibrotic processes. In the kidneys, ACE2 is primarily expressed in renal tubular epithelial cells, particularly in the proximal tubules. Research has shown that ACE2 expression is upregulated in certain kidney diseases, such as diabetic nephropathy and chronic kidney disease. This has led to investigations to decrease ACE2 levels and/or use MasR agonists/antagonists to modulate the activity of the ACE2-Ang(1–7)-MasR axis to improve renal and cardiovascular disease ^[29][41]. ACE2 has been reported to be a tumor suppressor gene in diverse cancers, however, in breast invasive and thyroid carcinoma, in prostate cancer, liver hepatocellular carcinoma, kidney chromophobe, and stomach adenocarcinoma it was considered an oncogene [15]. However, studies examining ACE2 expression in renal cancer are very few, many showed in silico analysis and overall have reported mixed results. ccRCC is the most common kidney tumor in adults (about 75% of incidence) and originates from the renal tubule ^[30][44]. In silico analysis reported that ACE2 was at low expression levels in ccRCC, where the high expression was associated with a favorable overall and disease-free survival ^[31][45]. However, recent research studies reported high ACE2 expression levels, in particular in papillary (94%) and clear cell (86%) renal carcinoma ^{[32][33][34][35]}[28,48,49,50]. The variability in ACE2 expression in renal cancer cells has raised questions about whether there could be differences in susceptibility to SARS-CoV-2 infection among individuals with RCC. It’s important to note that ACE2 expression is just one factor in determining susceptibility to infection, and other factors, such as host immune responses, also could play a role. It has been reported that the Ace2 gene resides on chromosome 16 and in the kidney it is tightly controlled by an upstream genetic locus on the same chromosome consisting of six genes whose expression is highly correlated with that of ACE2 ^[33][48]. The expression of ACE2 and the co-variants are involved in the RAS signaling which has a renal protective function, in particular, ACE2 and PDGFC are co-expressed and play an important role in the renal physiology and morphology ^[33][48].

2.2. Transmembrane Serine Protease 2 (TMPRSS2)

3.2. Transmembrane Serine Protease 2 (TMPRSS2)

TMPRSS2 is a cellular protease that primes the spike protein of SARS-CoV-2, enabling the virus to enter host cells more efficiently. TMPRSS2 is also expressed in the kidneys, primarily in the proximal tubules. Its expression in renal cells, like ACE2, can influence the ability of SARS-CoV-2 to infect these cells. The expression of TMPRSS2 in cancerous kidney cell lines, such as those found in renal carcinoma tissues can vary. There is no in-depth literature on this topic however some studies have shown that the expression of TMPRSS2 can be altered in various types of cancer. At the experimental level, Choong and colleagues analyzed the expression of ACE2, TMPRSS2, and NRP1 proteins in RCC by immunohistochemistry of tissue microarray (TMA) by using 263 cases of CCRCC, 139 of pRCC, 18 of CHRCC, and human kidney tissue as controls ^[32][28]. They reported that CCRCC tissues were positive at 76%, 81%, and 85% for ACE2, TMPRSS2, and NRP1 respectively. pRCC showed 93%, 56%, and 66% positivity for ACE2, TMPRSS2, and NRP1. CHRCC was negative for ACE2 and NRP1 but showed a weak TMPRSS2 positivity in 50% of the tissues ^[32][28]. Mechanisms of TMPRSS2 downregulation in cancer are not yet known. In Head and neck squamous cell carcinoma (HNSCC), an aberrant upregulation of a group of specific microRNAs has been highlighted that could target TMPRSS2 at a post-transcriptional level reducing its levels in the tumor ^[36][56]. The fact that TMPRSS2 expression is low does not lead to an automatic decrease in the possibility of infection. Preclinical studies on prostate cancer have demonstrated that while the pharmacological inhibition of androgen receptor decreases the expression of TMPRSS2, in parallel it induces the expression of ACE2, increasing the risk of SARS-CoV-2 infection [10]. This reasoning can be translated throughout the complex network of regulations within a tumor cell. The expression of ACE2 and TMPRSS2 in kidney cells has raised questions about the susceptibility of individuals with kidney-related diseases, including kidney cancer, to SARS-CoV-2 infection. Recent studies revealed that other SARS-CoV-2 factors such as ANPEP (alanyl aminopeptidase, membrane), ENPEP (glutamyl aminopeptidase), and DPP4 (dipeptidyl peptidase 4) are expressed at high levels in renal cancer, especially in ccRCC. 

2.3. SARS-CoV-2 Infection and Renal Cancer: Oncolytic Properties and Improvement of Antitumor Immunity

3.3. SARS-CoV-2 Infection and Renal Cancer: Oncolytic Properties and Improvement of Antitumor Immunity

Oncolytic viruses are a group of viruses that can lead cancer cells toward death, so they are employed for anti-cancer immunotherapy, including therapy for renal cell carcinoma ^{[37][38][39][40]}[60,61,62,63]. Very recently Fang and colleagues reported that combined treatment of carbonic anhydrase 9 (CA9)-targeted CAR-T cells with an oncolytic adenovirus carrying the chemokine (CC motif) ligand 5 (CCL5), cytokine interleukin-12 (IL12) induced moderate inhibition of xenografted tumor in nude mice and increased infiltration of CD45+CD3+ T cells and prolongation of mouse survival in immunocompetent mice ^[41][64]. While the oncolytic activity of various viruses has been known and has been exploited for years for the therapy of renal cancer ^{[37][38][39][42]}[60,61,62,65], practically to date the papers published by searching with the words key “oncolytic AND SARS-CoV-2 AND renal cancer” are two, one of which is unrelated to the topic ^[32][43][28,66]. The exciting question that many research groups are eager to answer is whether SARS-CoV-2 directly affects tumor cells or generates a greater state of immunogenicity. For example, recombinant poliovirus injected into human breast cancer, melanom, and prostate cancer cell models can increase immune activity in the tumor microenvironmental ^[44][67]. As previously commented, Choong and colleagues suggested two scenarios: one of an oncolytic type mediated by the virus on ccRCC cells exposed to the SARS-CoV-2 Delta variant and in those of the tumor of the patient with COVID-19 infection followed by nephrectomy; a second where viral infection of tumor cells induces antigen expression and a greater immune response ^[32][28]. Although the results of the expression of SARS-CoV-2 receptors and its interactors in ccRCC and pRCC are clear, the studies conducted so far not only on kidney tumor models but also on other cancers are too few and above all, they make use of in silico analyses which should then be supported by robust validation experiments. Therefore, drawing conclusions regarding potential treatments for RCC by exploiting this preliminary knowledge on the effects of SARS-CoV-2 viral infection is premature. 

34. Mortality Risk and Severity of COVID-19 in Advanced Renal Cancer Patients

Cancer has been included among the major risk factors for death in patients infected with COVID-19, so during the pandemic, several cancer societies developed and regularly updated specific guidelines for cancer care ^[45][68]. However, in the face of this crucial action, it is well known that screening and diagnostic programs, also for cancer care, were severely affected during the pandemic, with consequent higher prevalence of more advanced-stage presentation ^[46][47][48][69,70,71]. Different factors are responsible for the increased risk of death in patients with cancer and COVID-19, especially in individuals in an advanced stage. Among these influencing factors, undoubtedly, the dysfunction of innate and humoral immunity, depending on therapies with immunosuppressive effects, and the presence of comorbidities, play a key role. The observational prospective study ESMO-CoCARE, including data from 1626 patients with solid/hematological malignancies collected since June 2020, validated previously published observations on variables associated with COVID-19 outcomes in patients with cancer. Interestingly, the authors found that Asian ethnicity and higher BMI are associated with better COVID-19-related outcomes, suggesting that the “obesity paradox”, host genetics, and human leukocyte antigen profiles may influence COVID-19 outcomes ^{[43][49][50][51]}[66,72,73,74]. A widely debated topic in literature is the association between anti-tumor therapies and severity and mortality in cancer patients with COVID-19. Although the immunologic implications and the high proinflammatory status of advanced cancer worsen the severity and mortality of COVID-19 infection in cancer patients, it is undeniable that systemic anticancer therapy increases the level of complexity, further worsening the outcome. Divergent and contradictory results emerge from these studies, probably because of heterogeneity related to the class of therapies, the time variability between treatment and COVID-19 diagnosis, and the type of cancer.  Immunogenicity is a peculiar characteristic of renal cell carcinoma since this neoplasm is often diffusely infiltrated by CD8⁺ T lymphocytes, macrophages, neutrophils, and dendritic cells ^[52][79]. Therefore, in recent years, the discovery of ICIs, in monotherapy or combination with other drugs, has revolutionized the treatment of advanced renal cell carcinoma. ICIs work by blocking lymphocyte receptors (such as PD-1 or CTLA-4), namely the ligand on the tumor cell (PDL-1), thus reactivating the physiological anti-tumor response ^[53][54][80,81]. However, just as it occurs for drugs with anti-angiogenic activity, many patients develop resistance to ICIs because the tumor cells can activate alternative inhibitory pathways or create an ‘immune cold’ microenvironment ^[55][56][82,83].  Overall, the data emerging from clinical studies and metanalysis show that the mortality rate associated with COVID-19 for patients with cancer varies from 13% to 33.6%, depending on many factors such as population heterogeneity and a selection bias towards the most severe cases in some studies ^[43][66]. 

45. SARS-CoV-2–Related Genes as New Potential Prognostic Factors and Therapeutic Targets for Renal Cancer Cell Patients

A growing literature pointed out emerging topics regarding the role of SARS-CoV-2 infection in the progression of RCC and the research of predictive factors of cancer progression and new therapeutic strategies to counteract the complications of COVID-19-related and mortality risk. In ccRCC, using the TCGA dataset, Huang and colleagues identified 31 SARS-CoV-2-related genes differentially expressed between ccRCC and normal kidney tissues ^[57][87]. The interesting part of the study is that the authors selected 5 genes that were able to stratify low- and high-risk ccRCC patients with poor survival. Gene set enrichment analysis (GSEA) showed that some inflammatory/immune pathways were significantly enriched in the high-risk group, where patients belonging to the high-risk group had higher stromal and immune cell scores, thus purity of the lower tumor. Furthermore, these high-risk patients had high numbers of M0 macrophages, regulatory T cells, and T follicular helper cells and increased expression of the immune checkpoints CTLA-4, LAG-3, TIGIT, and PDCD1 compared to low-risk patients. In conclusion, this prognostic signature based on genes related to SARS-CoV-2 as reliable prognostic predictors for ccRCC patients is very promising and indicates a precise road of future research that is inseparable from massive sequencing studies ^[57][87]. During the pandemic, different medicinal plants/herbs and phytocompounds with immunomodulatory, anti-viral, and anti-inflammatory properties have been proposed in the treatment of COVID-19 ^[58][94]. A particular interest has been addressed to berberine in treating ccRCC/COVID-19 patients since it can inhibit SARS-CoV-2 infection and reproduction and reduce the inflammatory response in COVID-19 patients ^[59][60][95,96]. Recently some authors explored the berberine therapeutic mechanism in treating ccRCC/COVID-19 patients, and through gene ontology and protein-protein interaction (PPI) analysis, identified 26 target genes as potential berberine targets, involved in crucial biological processes in ccRCC/COVID-19 pathogenesis ^[61][62][97,98]. It has been reported that the severity of COVID-19 infection seemed to be strictly related to the over or downregulation of different genes involved in different roles of resisting viral infections ^[63][99], inflammation, and ROS production ^[64][100]. Thus, it has been postulated that these genes could be used as a prospective target for COVID-19 treatment. In conclusion, this prognostic signature based on genes related to SARS-CoV-2 as reliable prognostic predictors for ccRCC patients is very promising and indicates a precise road of future research that is inseparable from massive sequencing studies.