In most cases, virus multiplication in host cells can block protein synthesis and DNA replica- tion of the cells, leading to cell metabolism disorder, while massive replication of virus causes damage to numerous cellular organelles (13,14). After the replication, large numbers of progeny viruses are then released from the cells, resulting in lytic cell death referred to as a destructive process (14,15). Conversely, certain viruses known as 'tumor viruses' do not cause the destruction of infected host cells. Instead, tumor viruses can control the complex genome of host cells, promoting unrestricted cell proliferation (13-15). Experiments on induction of chicken sarcoma by Rous virus demonstrate that virus infection can successfully induce tumor formation (16,17), showing that tumors can either develop spontaneously in organisms or be formed by virus induction. The above observation has laid a foundation for the following in vitro tumor cell cultures and in vivo transfection in mice. It has been shown that infection of Rous virus leads to the occurrence of tumor cell traits in the cultured cells in vitro, which include a loss of contact inhibition, continued proliferation and anchoring independence (17). To date, several tumor viruses have been identified, including human herpes virus 8 (HHV-8) (18-20), human papilloma virus (HPV) (19,21-27), hepatitis B virus (HBV) (19,28-30), Epstein-Barr virus (EBV) (19,26,31-35), Cytomegalovirus (CMV) (19,27,36-38), human immunodeficiency virus (HIV) (19,39-42), human T cell lymphotropic virus (HTLV) (43,44) and hepatitis C virus (HCV) (45-48) (Fig. 1).

Viruses have a very small genome in which most genes encode proteins involved in virus replication, while only a very small portion of the genes may be related to tumor cell transformation (27). The carcinogenic mechanism of tumor viruses has not yet been fully elucidated, which may be related to the destruction of host cell genetic stability, cell gene phenotype changes and virus latency/reactivation. These mechanisms are not inde- pendent and there are complex connections between them. Although different tumor viruses encode different virus products, they can target some of the same mechanisms, such as inhibiting tumor suppressor gene expression, abnormally activating oncogenes to interfere with cell growth and differentiation-related signals including NF-κB, telomerase reverse transcriptase (TERT), tumor necrosis factor receptor associated factors (TRAFs), PI3K-AKT-mTOR, β-catenin and interferon signaling pathway, thereby affecting cell growth cycle regulation and inducing malignant cell transformation (49-51). DNA viruses encode viral oncogenes and RNA viruses can directly encode oncogenes or activate cell oncogenes through cis- or trans activation. Centrifugation-based measurement of the molecular mass of nucleic acids reveals that viral nucleic acid sequences co-sediment with host nucleic acid macromolecules, indicating that viral nucleic acids have become integrated into host chromosomes, constituting the cellular genome (52). It is noteworthy that instead of the whole nucleic acid sequence of viruses, only a part of the sequence with oncogenic role becomes integrated into the cellular genome. In these cases, part of single-strand RNAs in the genome of RNA viruses are reverse-transcribed into double-strand DNAs that are subsequently integrated into host chromosomal DNAs. These integrated viral double-strand DNAs are known as proviruses (53).

The genome of organisms harbors a large number of proto-oncogenes, such as Myc, c-Kit, Raf, Ret, H-ras and K-ras (54-58). Among >30 proto-oncogenes identified to date, most have derived their names from the respective viruses in which they were originally discovered. Once proto-oncogenes in the genome of organisms are captured and activated by the respective viruses, malignant transformation of cells will occur (59). Retroviruses containing oncogenes can capture and activate proto-oncogenes. By contrast, retroviruses without oncogenes activate proto-oncogenes by inserting their own genomes adjacent to those genes (insertion mutations) (60). It has been demonstrated that this insertion is not random and the insertion sites of retrovirus double-strand DNAs (proviruses) are closely adjoined to the proto-oncogenes (60), suggesting the presence of a mechanism underlying the recognition of proto-oncogenes in retroviruses. Under this circumstance, integrated transcriptional promoter of the viral genome causes a damage to the regulatory mechanism of proto-oncogene expression, enabling the expression of cellular genes under the control of the viral promotor and eliciting a constitutive expression of proto-oncogenes (61-63).

In addition to changes in proto-oncogenes and tumor suppressor genes, the origin of tumors also includes the effects on host cell gene stability and gene phenotype. Tumor viruses can inhibit the expression of host tumor suppressor genes and interfere with cell cycle regulation by affecting the form of DNA methylation and histone modification (64,65). In addition, the virus has caused damage to cells before entering the incubation period, resulting in permanent genetic and epigenetic changes in the cells; the virus entering the incubation period may reactivate and cause damage to the cell (64, 65). The virus may experience latency/reactivation cycle changes and the cells surviving continuous damage continue to accumulate DNA damage during this period and then a series of effects such as genetic instability, cell immortalization and tumors occur (66).

Given that patients with cancer and COVID-19 are characterized by high mortality (92), it is recommended that these patients continue to take anticancer drugs orally during the COVID-19 pandemic. However, the antitumor therapy should be undertaken carefully and reasonably, while postponing adjuvant chemotherapy or selective operation needs to be considered on a discretionary basis to avoid the aggravation of pneumonia symptoms (93). In addition, it has been shown that patients with COVID-19 and a history of cancer who are undergoing an active treatment have a higher risk of developing a severe event than those without cancer (94). It is noteworthy that during the hospitalization, the mortality risk of those patients recently undergoing antitumor therapy is 4 times as high as that of general population (88). In addition, targeted therapy or immunotherapy could lead to a 3.29-fold increase in the risk of developing a severe and critical COVID-19 (88). Notably, among all patients with COVID-19 and cancer receiving various therapies, those undergoing immunotherapy displayed the highest mortality rate as well as the most severe case (88). This increase can be attributed to the enhancement in immune system-mediated attack against SARS-CoV-2 in the later stage of the virus infection, which aggravates the lung damage and then elicits severe symptoms (Fig. 4) (95). In addition, pneumonia accounts for 42% of all death cases caused by the side effects of programmed death-1 (PD-1) antibodies (96). Similarly, either autologous and allogeneic hematopoietic stem cell transplantation or chimeric antigen receptor T cell therapy may lead patients with cancer to be highly susceptible to SARS-CoV-2 infection (88).

By contrast, it has also been demonstrated that blockage of PD-1/PDL-1 pathway can inhibit acute or chronic viral infection to a certain extent. An elderly patient infected with SARS-CoV-2 took nivolumab for metastatic malignant melanoma in the meantime. Surprisingly, considering her age, complications and cancer diagnosis, her virus infection condition was well controlled and no pneumonia was developed (97). This may be attributed to nivolumab-induced blockage of PD-1/PDL-1 pathway and its anti-viral effect. In addition, use of immune checkpoint inhibitors (ICIs) for the cancer treatment is getting more and more prevalent. However, ICI-caused recovery of immune function in patients with cancer may lead to generation of potential lung toxicity, thus aggravating COVID-19 and acute respiratory distress syndrome (ARDS) (98,99). Tocilizumab has been shown to be successfully applied for treatment of the immune-related adverse event (irAE), such as arthritis in patients undergoing ICI treatment (100). As a monoclonal antibody raised against IL-6 receptor, tocilizumab may serve as a potential neutralizing antibody for COVID-19 treatment (95,101,102). Thus, the study of ICI and tocilizumab may provide some new thoughts for overcoming the side effects of irAEs in patients with cancer and COVID-19. In addition, the PD-1 block did not appear to affect the severity of COVID-19 in lung patients with cancer after the risk factors for smoking were excluded (103). Despite all these observations, whether or not ICIs including PD-1 antibody should be given to patients with cancer during SARS-CoV-2 infection needs to be determined based on larger scale clinical analysis, including the perspectives of immune function of patients, tumor type, tumor stage, antiviral efficacy of drugs and so forth. For patients who need to receive cancer treatments, assessment of the immune function of patients based on immune deficiency score index, strengthening nursing care of patients prior to the recovery of immune function and early vaccination against respiratory pathogens, such as seasonal influenza and streptococcus pneumoniae, should be carried out (104).

During the COVID-19 pandemic, chemotherapy can only be applied to patients with cancer unless immunosuppression, blood toxicity, pneumonia/interstitial lung disease and other serious risks caused by chemotherapy are reduced (94). For example, when chemotherapy regimens with moderate/high risk of immunosuppression (e.g. anthracyclines, docetaxel, cisplatin or carboplatin 3 times a week) are administered to patients with triple-negative breast cancer, it is recommended that the patients should be supplemented with preventive hematopoietic growth factors to reduce the risk of suffering from neutropenia (105). Application of steroids needs to be strictly controlled to prevent an increased risk of immunosuppression. During the pandemic, the oral preparation is usually the first choice for adjuvant bisphosphonates. Low-dose oral medication such as capecitabine and vinorelbine should be considered preferentially in choosing the chemotherapy regimen for avoiding hematological toxicity (94). In case intravenous injection is considered unavoidable, preferential use of liposome preparation of anthracyclines and prolonged dosing interval of intravenous injection should be applied.

It has been suggested that during the COVID-19 outbreak, RT-hypo can be applied for the treatment of neck squamous cell carcinoma (HNSCC) patients with a relatively lower risk of distant metastasis (106). It is proposed that RT-hypo be considered in place of concurrent chemoradiotherapy for HPV+T1-T3N0-N2c (TNM-7) HNSCCs, HPV-T1-T2N0 HNSCCs and selected stage III HNSCCs during the outbreak (106). When shorter and fewer hospital visits, as well as avoidance of immunosuppressive chemotherapy, are needed to reduce the risk of SARS-CoV-2 infection, RT-hypo or short fractionated radiotherapy may provide a more appropriate regimen for patients with non-metastatic cancer. Therefore, it is necessary to assess the risk of disease progression for those patients who do not receive a timely and effective antitumor therapy. In this case, a timely diagnosis and tumor treatment should be applied to those patients with a rapidly progressed cancer such as lung cancer, pancreatic cancer, leukemia and highly invasive lymphoma. By contrast, targeted tumor therapy may be postponed for patients with thyroid carcinoma, breast cancer, or other carcinoma at a relatively low risk of disease progression. Particularly, for hospitalized elder tumor patients with COVID-19 or patients complicated with other basic diseases, early clinical monitoring should be strengthened, while timely and effective tumor intervention measurements need to be formulated. If possible, priority should be given to minimally invasive surgery because compared with open surgery, minimally invasive surgery can shorten the duration of hospitalization and improve the recovery of patients with cancer, thereby reducing the risk of SARS-CoV-2 infection in hospital (67).

Some evidence suggests that therapeutic drugs for prostatic cancer may serve a synergistic role in treating COVID-19 (107). Inhibition of androgen signaling is considered the symbolic therapeutic strategy of prostatic cancer, while androgen inhibitors (e.g. leuprolide) and androgen receptor (AR) signaling inhibitors (e.g. enzalutamide, apalutamide and darolutamide) constitute the basis for the treatment of prostate cancer (107). In particular, either inhibition of AR expression and transcription or blockade of CYP17 using abiraterone provide a new perspective for the treatment of hormone-independent prostatic cancer (107). Transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) have been identified as the key targets for enhanced entry of SARS-CoV-2 into host cells (72,108,109). In addition, AR signaling has been demonstrated to promote the expression of TMPRSS2 (107). Thus, inhibition of AR signaling for treating prostatic cancer may suppress infection of SARS-CoV-2 in host cells by downregulating TMPRSS2, thereby preventing and treating COVID-19 (Fig. 5). However, preclinical studies have demonstrated that while inhibition of AR decreases the expression of TMPRSS2, it may lead to an upregulation in the expression of ACE2, increasing the risk of SARS-CoV-2 infection (107). Therefore, the potential negative outcome caused by inhibition of AR needs to be further evaluated.

It has been reported that patients with various cardiovascular diseases, diabetes or hypertension have an elevated level of ACE2, while displaying a relatively high risk of dying from COVID-19 (110). Notably, the expression level of ACE2 in kidney is higher than that in other organs; the level in kidney can be 100 times as high as that in lung (110). Thus, studies on shared molecular markers and overlapping signaling pathways between renal cell carcinoma (RCC) and COVID-19 will be of great clinical significance for the treatment of RCC patients complicated with COVID-19. Administration with ACEIs can reduce the tumor growth and metastatic potential, prolonging the survival period of patients with RCC. In addition, ACE2 inhibition leads to decreased ACE2 available for binding with the viruses (111-113), probably reducing the susceptibility of patients with RCC to SARS-CoV-2. Likewise, inhibition of ACE2 in other types of malignancies can effectively block the entry of SARS-CoV-2 into host cells. Cancer cells in general express higher levels of ACE2 compared with their adjacent normal cells and thus can be potentially more susceptible to SARS-CoV-2 infection (3). Since cancer cells have managed to evade host immune response in the first place, this may provide a better microenvironment for SARS-CoV-2 replication in cancer cells/tissues, which may partly explain why patients with cancer seem to be more susceptible to SARS-CoV-2 infection (87). Although ACEI-caused decline in bradykinin degradation may stimulate the growth, survival and migration of cancer cells, these effects can be finally counteracted by decreased expression of VEGFs due to ACEI-caused reduction in Ang II level and angiogenesis (110).

It has been shown that the expression of tissue factor in tumor cells can promote tumor growth and angiogenesis, thereby resulting in release of coagulant particles into circulation system, which subsequently trig- gers thromboembolism in patients with cancer (114). Given that concomitant infection with COVID-19 and hypoxia in patients with cancer lead to a higher risk of developing a thrombotic event, anticoagulant therapy could serve as one of preventive and treatment strategies for patients with cancer and infected with COVID-19 (115). It is thought that early administration of heparin can defer the dramatic increase of inflammatory biomarkers and downregulate coagulation state. A retrospective study conducted in China investigated 449 patients with severe COVID-19, among which 272 suffered from one or more chronic underlying diseases such as hypertension and heart diseases. In that study, patients underwent the treatment with various forms of heparin and a relatively lower mortality rate was observed in patients treated with heparin (40% vs. 64.2%, P=0.029) (116). Similarly, statins with anti-inflammatory, anti-thrombotic and immunomodulatory effects may reduce the risk of cardiovascular complications and thromboembolic events in patients with COVID-19 (117). In addition, ACEI, angiotensin receptor blockers, CCR5 treatment (118-120), tyrosine kinase inhibitors (TKIs) (121-125), bevacizumab (126,127), ruxolitinib (126,128), carmofur (126,129) and toremi- fene (126,130) could potentially be used as cancer therapy regimens aimed at counteracting COVID-19 mechanistically (Table I).

Notably, SARS-CoV-2 RNAs have been detected in the feces of certain patients with COVID-19 (131). Thus, diversity of intestinal flora and the presence of intestinal probiotics may serve an important role in assessing the disease course of COVID-19 (132). Patients with cancer usually display a compromised immune function as well as general imbalance of intestinal flora, which are very likely to aggravate the clinical manifestation of COVID-19 (132). Therefore, the recovery of patients with cancer infected with SARS-CoV-2 could be promoted by the administration of effective probiotics (e.g., fructooligosaccharide (FOS), galactooligosaccharides (GOS) and various Lactobacillus strains), which are selected based on analysis of intestinal flora in these patients. Alternatively, patients with cancer can take special probiotics for improving intestinal dystrophy, enhancing immunity and preventing against SARS-CoV-2 infection. Studies on effects of SARS-CoV-2 on the intestinal ecosystem in patients with cancer will provide new ideas for preventing and controlling the viral infection of patients with declined immunity such as patients with cancer.

Vitamin D is a fat-soluble vitamin that can be obtained from the diet, the classic role of which is to promote bone remodeling (133). Serum levels of 25-hydroxyvitamin D [25 (OH) D] have been shown to be negatively associated with a higher risk of colon, breast, prostate, stomach and other cancers (134). Vitamin D deficiency has been proved to contribute to the occurrence and progression of a number of cancers, so maintaining adequate serum vitamin D levels may be beneficial for cancer prevention and treatment (134). Recent studies have reported a significant association between the average level of vitamin D and the number of patients with COVID-19, especially the mortality rate (133,135-137). Vitamin D deficiency is present in >80% of patients with severe COVID-19 and is associated with poor prognosis (133,136). Vitamin D deficiency may contribute to the exacerbation of COVID-19 through inducing thrombotic effects and immune dysregulation (136). In immune response, vitamin D-dependent antimicrobial pathways are known to respond to double-stranded RNA produced in replication processes of SARS-CoV-2 (136,138). These path- ways subsequently upregulated the autophagy of damaged cells, as well as levels of various antimicrobial and antiviral peptides (136,138). Thus, vitamin D deficiency may predispose a host to SARS-CoV-2 infection by blocking the activation of above defense pathways and the migration of lymphocytes and macrophages (136). These findings suggest that vitamin D may protect the body from acute respiratory infections, while elderly patients with cancer and extreme vitamin D deficiency may be more susceptible to COVID-19. In addition to vitamin D, adequate levels of vitamin C and E are also essential to reduce the burden of symptoms and shorten the duration of respiratory infections during the COVID-19 pandemic (137). Micronutrients such as selenium and zinc, the dietary supplements in multivitamin tablets, not only serve important roles in cancer progression and therapy, but can also increase the immune responses against viral infection (138,139). It is speculated that selenium and zinc may also have a potential inhibitory effect on COVID-19 infection (137,138). Thus, regular supplementation of vitamin and other micronutrients may improve severe COVID-19 symptoms and survival in elderly patients with cancer. However, it is worth noting that further research is needed to determine the effective dose of vitamin and micronutrients supplements to help patients with cancer alleviate the symptoms of COVID-19.

At present, there are differences in the COVID-19 vaccination policy for patients with cancer. In some countries, the COVID-19 vaccine is not recommended for patients with malignant tumors, or even as a contraindication for vaccination (140). The main reason is the lack of clinical data on COVID-19 vaccine for patients with cancer, so the safety status, effectiveness and immune response after vaccination cannot be evaluated. However, recent reports show that even for patients with cancer, if there are no contraindications to the vaccine components, they may still receive COVID-19 vaccination and get sufficiently high immunogenicity (141-143). Although patients with cancer may have a delayed response to the vaccine, it may still bring some benefits, which is important for reducing the risk or severity of SARS-CoV-2 to patients with cancer (141,142). However, certain treatments for cancer, such as chemotherapy or immunotherapy, can weaken the immune system and may increase the risk of COVID-19 infection (144). Therefore, patients with early malignant tumors who have completed radical treatment and are not receiving anti-tumor therapy, can be vaccinated with COVID-19 vaccine; for patients with malignant tumors who are receiving chemotherapy, targeted therapy or immunotherapy, the vaccine should be used with caution; for patients with malignant tumors who are receiving endocrine therapy, the vaccine can be given to those in good health, while is not recommended for patients in poor health, whether or not they are receiving anti-tumor therapy (141,145). In the case of breast cancer, inactivated vaccines are recommended during breast cancer rehabilitation, including endocrine therapy and HER2 targeted therapy; whereas for patients undergoing surgery, chemotherapy and PD-1 treatment, it is recommended to wait for the sufficient clinical evidence to prove the safety and effectiveness before vaccination. For patients with cancer and impaired immune function, it is recommended to vaccinate live attenuated vaccines and recombinant subunit vaccines; and it is recommended to weigh the benefit and the risk before vaccinating with adenovirus vector vaccines (142). Notably, due to the low immune function, the degree of immunity of patients with cancer after vaccination is still uncertain. Patients with cancer vaccinated should continue to follow current guidance to avoid COVID-19 infection.

Oncolytic viruses are a class of natural or genetically-modified viruses that are capable of self-replicating and killing cancer cells (146). After infecting cancer cells, oncolytic viruses will replicate massively in the cells and promote the lytic cell death during the replicative process (Fig. 6) (146-149). At present, the latest clinical regimen for combined therapy of oncolytic viruses involves a combination with PD-1/PD-L1 antibodies, providing effective and individualized tumor specific oncolytic immunotherapy to patients with cancer who are resistant to PD-1/PD-L1 blockade therapy (149,150). Notably, it has been shown that oncolytic viruses can trigger antiviral response of the immune system to increase the level of interferons in the tumor environment, thereby promoting PD-L1 production for the immune evasion (Fig. 7) (149).

It has been shown that ACE2 serves as a key target for SARS-CoV-2 infection of host cells (3,110). As NK cells massively express ACE2, they are easily infected by SARS-CoV-2, resulting in a decline in cell numbers as well as loss of immune function (151). Certain RNA viruses causing acute pulmonary infection have been found to promote apoptosis in NK cells (12). Notably, elevated levels of IL-6 and IL-10 caused by SARS-CoV-2 infection lead to a marked decrease in the cytotoxicity of NK cells, while SARS-CoV-2-induced release of IL-2 and TNF-α recruits NK and T cells into the tumor tissue (12). Based on the above observations, it is hypothesized that excessive production of proinflammatory cytokines during COVID-19 infection may serve a pivotal role in lymph node clearance. The depletion and inactivation of NK cells could serve as a therapeutic regimen for NK lymphoma patients who are resistant to conventional chemotherapy and improve the signs and clinical symptoms of the patients with cancer. In addition, the viral copy number of EBV-DNA, a sensitive biomarker of NK/T cell lymphoma, has been shown to be markedly declined during the course of COVID-19 (12). In addition, serum copy number of EBV-DNA, cell number of NK cell clones and recurrence rate of lymphoma in patients with NK lymphoma are increased after the subsiding of SARS-CoV-2 infection (12), indicating that COVID-19 infection can defer the tumor progression of NK lymphoma patients. The binding between SARS-CoV-2 and the respective receptors such as ACE2 in NK cells may determine its targeting of oncolytic adenoviruses. All these observations suggest that while SARS-CoV-2-induced immune response exerts an anti-tumor effect to a certain extent, SARS-CoV-2 displays potential oncolytic characteristics for lymphoma patients.

In addition, recent studies have suggested that SARS-CoV-2 infection may protect against Hodgkin's lymphoma by eliciting an anti-tumor immune response (149). Shortly after having been diagnosed with advanced Hodgkin's lymphoma, a 61-year-old man with severe kidney disease who was on long-term dialysis had been confirmed with COVID-19 infection (149). After 11 days hospitalization, he was discharged and returned home for rehabilitation. No corticosteroids or immunochemotherapy was received during his hospitalization and rehabilitation. However, four months after being discharged from the hospital, CT reviews of the patient demonstrated reduced palpable lymphadenopathy, interim PET/CT scans displayed the extensive retrogression of lymphadenopathy and an overall reduction of metabolic absorption and levels of tumor-related biomarkers decreased by >90% (149,152). This medical report suggests that possible mechanisms of oncolytic responses of SARS-CoV-2 may cover cross reactions between pathogen-specific T-cells and tumor antigens and the activation of natural killer cells through inflammatory cytokines generated during response to the infection of SARS-CoV-2. In addition, the majority of tumor patients suffer from nephropathy, diabetes and other complications and oncolytic virus therapy can partially offset the hepatorenal toxicity and metabolic disorders caused by chemotherapy and immunosuppressive agents. At present, studies provide evidence that combination therapy with oncolytic vaccine and toxoid can help initiate anti-tumor immune response of the immune system via CD4+ memory T cells. Therefore, if oncolytic characteristics of SARS-CoV-2 could be combined with the memory of T cells by genetic modification to recall the immunity of known antigens to coronavirus, this scenario may provide a new approach for the genetic modification of oncolytic viruses.