Oral health may be directly linked to the success of cancer treatment: studies have shown that oral microorganisms can impact both carcinogenesis and the way the body responds to cancer therapies.
To better understand this topic, C2PO spoke with Professor Henrique Rinaldi Matheus, from the Discipline of Periodontics in the Department of Stomatology at the School of Dentistry of the University of São Paulo (FOUSP).
Professor Henrique Rinaldi Matheus obtained his degree in Dentistry from São Paulo State University (UNESP) in 2016 and earned both his Master’s (2019) and Ph.D. (2023) in Periodontics from the same institution. In 2021 and 2022, he completed a research fellowship at Harvard University, in the United States.
C2PO: Can all oral health conditions be related to cancer and its treatment outcomes?
Professor Henrique Rinaldi Matheus: An oral condition called periodontitis has emerged as a potentially relevant factor associated with cancer development and with oncological treatment outcomes and toxicities. Periodontitis is characterized as a chronic inflammatory disease that affects both the lining tissues (gingiva) and the supporting structures of the tooth (cementum, periodontal ligament, and alveolar bone). Although it is a multifactorial condition, the dental biofilm — whose accumulation is favored by poor oral hygiene — is an essential element for its onset and progression. Recent research indicates that inflammatory mediators and bacterial components released during periodontitis can reach the bloodstream, affecting systemic health and contributing to the worsening of several conditions. A particularly concerning fact is the high global prevalence of severe periodontitis, which affects more than one billion people worldwide. It is worth noting that this distribution is not homogeneous, as periodontitis is more prevalent in low- and middle-income countries.
C2PO: What are the main relationships between periodontitis and the risk of developing tumors? And which types of cancer are most related to periodontitis?
Professor Henrique Rinaldi Matheus: The main associations between periodontitis and carcinogenesis have been investigated in the context of the oral microbiome. The key mechanisms by which the periodontitis-associated microbiome may promote cancer development are: (1) impairment of epithelial barrier function, (2) synthesis of bacterial metabolites and toxins (e.g., sulfides, acetaldehyde, deoxycholic acid, and colibactin), (3) induction of low-grade systemic inflammation, and (4) activation of cell proliferation. Intuitively, one might think that this influence would be locoregional, restricted to oral cavity cancers; however, the progression of periodontitis causes ulceration of the gingival epithelium, facilitating the entry of microbial and inflammatory products into the bloodstream, even leading to bacteremia. It has been shown that periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum can colonize distant sites such as synovial fluid, pancreas, intestine, lung, and even the brain.
In this regard, signatures of oral microorganisms have been identified in several types of tumors. Recently, it was observed that the distribution of these microorganisms — many of which are periodontal pathogens — in oral squamous cell carcinoma and colorectal cancer is not random but rather highly organized in niches with immune and epithelial functions that promote tumor progression. It was also shown that cancer cells infected by bacteria invade surrounding tissues as single cells and recruit myeloid cells to bacterially colonized regions. In such cases, since patients were not periodontally assessed or followed prospectively, it is not possible to establish the temporality of these events, but it is undeniable that these pathogens are altering the tumor microenvironment.
Furthermore, results from two large cohorts — the American Cancer Society Cancer Prevention Study-II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial — showed that the levels of three periodontitis-related pathogens were increased in the oral sites and fluids of patients who developed pancreatic cancer compared to those who did not.
A recent systematic review published in an oncology journal identified periodontitis as a potential risk factor for colorectal, oral, pancreatic, lung, and gastrointestinal cancers. The authors concluded that this association is not only epidemiological but also biologically plausible.
C2PO: In what ways can periodontitis impact the effectiveness of cancer treatments?
Professor Henrique Rinaldi Matheus:
The impact of periodontitis on treatment effectiveness seems to be more closely related to precision oncology — for example, resistance to immune checkpoint blockade. Several lines of evidence suggest that systemic immune reprogramming and activation occur in patients with periodontitis. Peripheral blood T cells from these patients express significantly higher levels of programmed cell death protein (PD)-1. Importantly, blocking the PD-1/PD-L1 interaction was not sufficient to restore the proliferative response of T cells, indicating that PD-1 blockade may be less effective in patients with periodontitis. Although this result is not yet fully understood, one possible explanation is that PD-1 expression remains elevated in these cells, contributing to T-cell exhaustion.
The complement pathway is also a crucial component of immune response, facilitating pathogen clearance through inflammation and recruitment of phagocytic cells. However, Porphyromonas gingivalis — a key pathogen in periodontitis — manipulates this pathway to evade immune clearance and sustain inflammation. Through gingipains that generate C5a, which in turn activates C5a receptors on various immune cells, the bacterium enhances inflammation while reducing phagocytosis. Patients with periodontitis present elevated serum levels of complement C3 compared with healthy individuals, and the C3aR and C5aR1 pathways have been shown to suppress effector T-cell functions. Studies have demonstrated that anti-PD-1 therapy was more effective in a preclinical sarcoma model in animals lacking C3 than in those with normal C3 expression, suggesting that high C3 levels impair antitumor responses. Similarly, the presence of C5a was found to reduce the efficacy of PD-1 blockade in colon adenocarcinoma models. These findings indicate that overexpression of complement components such as C3 and C5 in periodontitis may compromise the effectiveness of immune checkpoint blockade therapies, ultimately impacting immunotherapy responses.
In addition to resistance mechanisms, by altering host immune homeostasis, periodontitis may also lower the immune threshold for developing immune-related adverse events (irAEs) in cancer patients undergoing immunotherapy. This concept has not yet been deeply explored, but several autoimmune disorders overlap between periodontitis and irAEs associated with immune checkpoint blockade.
C2PO: In the context of Brazil’s Public Health System (SUS), is there a benefit to providing dental treatment to cancer patients, or should prevention be the main priority?
Professor Henrique Rinaldi Matheus: Prevention should certainly be a priority when it comes to structural changes in public oral health policies within the SUS. However, given the current prevalence and incidence of periodontitis in the Brazilian population, addressing this condition is essential, since most systemic markers of periodontitis return to homeostatic levels after periodontal treatment. Conversely, it is worth noting that periodontitis itself has been listed as a potential immune-related adverse event (irAE) associated with immune checkpoint blockade therapy.
Regarding other cancer treatments, such as radiotherapy and chemotherapy, oral manifestations like mucositis and dental caries are common, underscoring the importance of dental follow-up. In the case of periodontitis, preclinical studies in murine models have shown that antineoplastic agents exacerbate periodontal inflammation and disease progression, increasing the risk of tooth loss in a short period. This reinforces the need for periodontal diagnosis before initiating oncological treatment, as well as continuous follow-up during chemotherapy cycles to detect early signs of periodontal disease.
In addition, dental implants have become a common therapeutic option for tooth replacement, and a large portion of the Brazilian population now uses these devices. The same research group that studied the impact of chemotherapy on periodontal tissues also found in murine models that the repair and turnover processes around implant components are negatively affected by antineoplastic agents, suggesting that patients with implants could experience complications during cancer treatment — complications that could be prevented through regular dental care.
C2PO: What is the importance of integrating periodontics and oncology? Is this integration advancing, or is it still far from being achieved?
Professor Henrique Rinaldi Matheus: The impact of chemotherapy on the onset and progression of periodontitis and the resulting risk of tooth loss are strong reasons to promote closer integration between periodontics and oncology. Diagnosing and treating periodontitis before chemotherapy is crucial, but equally important is patient monitoring throughout oncological treatment.
In the era of precision oncology, the development of immuno-oncological drugs has transformed cancer care and improved survival for patients with various tumor types. However, these treatments remain inaccessible to most people in low- and middle-income countries, who could greatly benefit from them. A major step toward expanding access to immune checkpoint inhibitors in Brazil was proposed through Bill No. 5514/23, which guarantees cancer patients the right to immunotherapy through the SUS. Considering that periodontitis is more prevalent in low- and middle-income countries, periodontal treatment could bring significant benefits by improving immunotherapy response rates and reducing toxicity profiles among socioeconomically vulnerable groups — both in Brazil and globally.
Although the first studies investigating direct associations between periodontitis and immunotherapy resistance or toxicity are still being developed, the evidence available so far, even if indirect, is strong enough to justify a concerted effort to integrate periodontics and oncology.
Ultimately, the negative impact of nutritional status changes on mortality, morbidity, and quality of life among cancer patients underscores the importance of maintaining oral rehabilitation and masticatory function, highlighting that dentistry as a whole should play an active role in oncology.
