Editorial: Dormant Cancer Cells, Cancer Progression, and Post-Acute Sequelae of COVID-19 and Influenza

With the approach of autumn and winter in the northern hemisphere, public health services have begun to encourage the uptake of booster vaccines to prevent COVID-19 and seasonal influenza. However, as more time passes since the COVID-19 pandemic, vaccine uptake continues to fall [1,2]. Awareness of the long-term consequences of respiratory virus infections, particularly long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), has also lost momentum [3,4].

There have been several retrospective population studies to evaluate the benefits of COVID-19 vaccination to prevent SARS-CoV-2 infection, with mortality as the primary preventive outcome. In July 2025, Ioannidis and colleagues reported that the major overall benefits from COVID-19 vaccination during the years between 2020 and 2024 were lives and life-years saved, mainly for older persons, preventing 2.5 million deaths and saving 15 million life-years [5]. The most life-years saved (76%) were in individuals 60 years or older, which is a population that also has the highest risk of cancer diagnoses [5]. A more recent study by Meslé and colleagues from the World Health Organization (WHO) European Respiratory Surveillance Network of 54 countries reported similar findings, and these authors stressed the importance of up-to-date vaccination, particularly for the most at-risk individuals [6].

The COVID-19 pandemic and the effects of population isolation during lockdowns reshaped the epidemiology of other respiratory infections, including seasonal influenza [7]. Following a temporary but dramatic reduction in cases of influenza, the post-pandemic resurgence returned influenza to pre-pandemic levels, and with the emergence of new and potentially pandemic strains [7,8]. During the 2023 to 2024 influenza season in the US, an estimated 40 million individuals were diagnosed with influenza, with 470,000 hospitalizations and 28,000 influenza-associated deaths, mainly in the elderly, but also with fatal cases in children [7]. Influenza vaccine uptake was reduced from 2020 in the US, including in the 2023 to 2024 influenza season [7,9]. These findings highlight the need for influenza vaccination in all age groups [7]. Public attitudes to vaccination and prevention of influenza and COVID-19 could soon be affected by the increasing evidence from population studies and laboratory studies that following acute respiratory virus infection, long-term consequences can include the acceleration of cancer progression and activation of ‘dormant’ cancer cells [10,11].

The American Cancer Society (ACS) provides an annual estimate of the incidence and mortality rates for cancer in the US, through national registries and the National Center for Health Statistics [12]. In 2020, 1,806,590 new cases of cancer and 606,520 cancer deaths were estimated to occur in the US [12]. Previously, cancer-related mortality rates rose until 1991 and then gradually fell up to 2017, as the four leading cancers significantly declined (breast, lung, prostate, and colorectal cancer) due to improvements in early cancer detection and cancer treatment [12]. However, in 2025, according to the ACS, 2,041,910 new cases of cancer and 618,120 cancer deaths are projected to occur in the US, with cancer mortality rates generally declining, but with some disparities [13]. For 2025, cancer incidence has generally declined in men [13]. However, cancer incidence has risen in women, with rates in women aged between 50 and 64 years surpassing those in men, particularly for lung cancer [13].

A recent review article has highlighted the relevance and importance of real-world data and evidence in clinical medicine, including from population databases, registries, and biobanks [14]. An association between respiratory virus infection, including COVID-19, and increased cancer incidence and mortality has emerged from early anecdotal reports, and on assumptions about the effects of epidemic and pandemic lockdowns [10,15]. There is now increasing clinical and experimental evidence that respiratory virus infections from SARS-CoV-2 and influenza virus can drive the progression of cancer due to direct immunomodulatory effects from viral infection [10,16].

In 2024, Fedeli and colleagues reported the findings from an evaluation of cancer-related mortality reports during the COVID-19 pandemic, from death certificates and the US Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database [10,17]. After a decade of declining mortality rates from cancer in the US, registered age-standardized cancer-related deaths during 2020 to 2021 were 1,379,643, and mortality increased for all cancers [10].

Patients with early cancer may experience periods when the cancer is either dormant or is in the early process of dissemination or metastasis [18]. The phenomenon of cancer cell-targeted immune surveillance has been proposed to control or prevent early metastases [19]. However, tissue and systemic inflammation can promote cancer development and progression [20]. Deaths from common cancers, such as breast cancer and lung cancer, are caused by metastases that can follow long periods of tumor dormancy [18]. The mechanisms that disrupt the quiescence of dormant and early disseminated cancer cells are beginning to be understood [18].

The concept of cancer cell dormancy was first described almost 80 years ago by Willis and Hadfield as the temporary mitotic arrest and growth of cancer cells [21,22]. Cancer cell dormancy is now recognized to result from an equilibrium between tumor cell division and apoptosis, and provides an explanation for relapse and metastasis that can occur months, years, or decades after treatment [18,23]. Dormant cancer cells can escape immune surveillance, targeted therapy, and chemotherapy, resulting in metastases and relapse that account for a large proportion of cancer-related deaths [18,23]. The mechanisms that ‘awaken’ dormant cancer cells are still poorly understood. However, in the wake of the COVID-19 pandemic, the effects of respiratory virus infection on dormant cancer cells are receiving attention [11].

Severe COVID-19 is associated with activation of the innate immune response that leads to systemic inflammation and acute respiratory distress syndrome (ARDS) in the lungs, and inflammation may likely involve the microenvironment of cancer cells, including dormant cancer cells [24]. In July 2025, Chia and colleagues reported the findings from a study in mice infected with influenza and SARS-CoV-2, which resulted in the rapid loss of the pro-dormancy phenotype in breast carcinoma cells in the lung, and expansion of metastatic carcinoma cells within weeks [11]. The phenotypic expansion of carcinoma cells was dependent on interleukin-6 (IL-6) [11]. Also, after viral infection, the previously dormant carcinoma cells impaired lung T-cell activation, and CD4-positive T-cells sustained the metastatic burden in the lung by inhibiting CD8-positive T-cell activation and cytotoxicity [11]. At this time, these animal model findings support observational or real-world findings in cancer patient survivors from the UK Biobank databases that identified that SARS-CoV-2 infection was significantly associated with an increased risk of lung metastasis and cancer-related mortality [25]. Therefore, these new insights from epidemiology and experimental data support that respiratory viral infections that cause influenza and COVID-19 may drive the resurgence of cancer metastases, including lung metastases [11,26,27]. These findings also support that accelerated progression of cancer is a type of long COVID, or PASC [4,26,27].

Conclusions

Prevention of infection from respiratory viruses, including SARS-CoV-2 and influenza, should follow public health recommendations and vaccination programs to prevent morbidity, hospitalizations, and mortality, as well as to avoid long-term complications and sequelae. Recent studies have shown that these respiratory virus infections may awaken dormant cancer cells, which is a finding that could have profound implications for public health policy and implementation. Due to concerns with vaccine hesitancy, it may now be time to include individuals with a history of cancer, or who have a high cancer risk, among the most clinically vulnerable to the effects of SARS-CoV-2 infection and infection from other respiratory viruses.