Fungi and cancer: unveiling the complex role of fungal infections in tumor biology and therapeutic resistance

Abstract

Cancer remains one of the most significant causes of mortality across the world. Despite remarkable advancements made in early detection, therapeutic strategies, and the advent of immunotherapy in recent years, numerous challenges continue to hinder optimal outcomes. The development and progression of cancer are driven not only by genetic and epigenetic alterations within tumor cells but also by dynamic interactions occurring with the surrounding tumor microenvironment (TME). It is a highly complex milieu composed of tumor cells, non-tumor stromal cells, extracellular matrix components, immune cells, blood vessels, and diverse signaling molecules. Emerging evidence underscores the pivotal role of fungi in influencing cancer biology, including initiation, progression, immune evasion, and the modulation of TME. Fungi, which are omnipresent microorganisms, have traditionally been considered opportunistic pathogens. However, recent research highlights their broader impact on host immunity and their potential contributions to cancer pathogenesis. For instance, in patients with cancer, fungal infections not only exacerbate clinical complications but also create conditions conducive to tumor growth, metastasis, and immune escape by altering the immune microenvironment. In addition, fungal-derived metabolites and their interactions with host immune pathways can significantly modulate the efficacy of immunotherapies. These findings have spurred interest in exploring antifungal strategies as adjunctive approaches in cancer management, positioning antifungal therapy as a burgeoning area of oncological research. This review provides an in-depth exploration of the complex interplay between fungi and cancer. It examines the multifaceted role of fungal infections in tumor biology, the mechanisms through which fungi reshape the TME through immune modulation and their influence on immune-evasion strategies and therapeutic resistance. Furthermore, the potential for integrating antifungal therapies into comprehensive cancer treatment regimens has been highlighted, offering insights into novel avenues for improving patient outcomes.

Keywords: antifungal therapy; antifungal therapy fungi; cancer; fungal derived metabolites; fungal-derived metabolites; immunity; tumor microenvironment.

Figure 1

This illustration summarizes the primary therapeutic strategies employed in cancer management, including surgery, chemotherapy, radiotherapy, immunotherapy, and chimeric antigen receptor T-cell (CAR-T) therapy. Each modality targets the tumor from a distinct angle, aiming to remove, destroy, or modulate malignant cells and the tumor microenvironment. These approaches are often used in combination to enhance efficacy and reduce the risk of recurrence.

Figure 2

The alteration of mycobiome in abundance across different tumor sites. The composition of fungal mycobiome is altered in different body sites (e.g., colorectum, pancreas, stomach, liver, head and neck, lung, and breast) that are associated with tumorigenesis, serving as potential diagnostic or prognostic biomarkers to promote the study of the complicated mechanistic investigation of fungal involvement in carcinogenesis. ↓decrease; ↑increase. Pathways with dashed arrows represent hypothetical interactions yet to be validated in clinical studies (Dohlman et al., 2022; Su et al., 2024).

Figure 3

Various mechanisms through which fungi interact with cancer, including: (a) A sydowii activates immune responses through the CARD9 pathway, promoting the upregulation of IL-1 and myeloid-derived suppressor cells (MDSCs). By inducing the production of nitric oxide (NO), arginase, and reactive oxygen species (ROS), it impairs the effect of cytotoxic T-lymphocytes (CTLs) and increases the proportion of PD-1+ CD8+ T-cells. These immune responses may contribute to tumor progression, causing the proliferation of lung cancer cells. (b) The activation of Malassezia globosa triggers the mannose-binding lectin (MBL) pathway, the MBL (mannose-binding lectin) pathway initiates complement activation via MASP-1 and MASP-2, which cleave C4 and C2 to generate C3 convertase, leading to downstream immune signaling, promoting the development of pancreatic cancer. This process involves tumor proliferation, invasiveness, and immune modulation. (c) In murine models, C albicans infection has been shown to enhance IL-17 production via macrophage glycolytic reprogramming, subsequently activating ILC3 cells and promoting IL-22 secretion through the VEGF 3 pathway. While this cascade has been linked to increased tumor proliferation in experimental systems, its clinical relevance remains debated, and contradictory data suggest that IL-17 may have dual roles depending on cancer type and immune context (Aggor et al., 2020; X. Wang et al., 2023b). (d) Fungi enhance tumor cell adhesion to endothelial cells through interactions with tumor cell surface mannose receptors (MR), thereby facilitating the metastasis of cancer cells. This mechanism allows tumor cells to migrate from the primary site to metastatic sites, driving cancer progression. Pathways with dashed arrows represent hypothetical interactions yet to be validated in clinical studies (Heung et al., 2023; Riquelme and McAllister, 2021; Sheng et al., 2024; Soerens et al., 2023).

Figure 4

The role of various fungal metabolites in cancer development, involving processes such as DNA damage, immune suppression, cell proliferation, and metastasis. Specifically, it includes: (A) C albicans induces DNA damage through its metabolites acetaldehyde and nitrosamines. Acetaldehyde generates reactive oxygen species (ROS) mediated by calcium ions (Ca²⁺), leading to mitochondrial rupture, which further disrupts cell function and promotes cancer progression. (B) C albicans secretes candidalysin, which activates the NLRP3 inflammasome. This process regulates cell proliferation-signaling pathways, promoting tumor cell proliferation and advancing cancer progression. (C) Aspergillus secretes aflatoxins, leading to immune suppression and DNA damage. The immunosuppressive effect of aflatoxins creates a favorable environment for tumor cell proliferation and survival. (D) C albicans promotes the production of matrix metalloproteinases (MMPs) through its metabolites, thereby facilitating the metastasis of tumor cells. This process helps tumor cells traverse the basement membrane and spread to other tissues. Pathways with dashed arrows represent hypothetical interactions yet to be validated in clinical studies (Kozieł et al., 2021; Rushing and Selim, 2019).

Figure 5

The influence of fungi and bacteria on each other’s growth and metabolism in the gut microbiota. Fungi, by metabolizing various nutrients, impact bacterial growth and metabolic processes. In turn, the metabolites produced by bacteria influence fungal growth and activity. These interactions cause alterations in the gut microbiome, which, in turn, modulate the local immune microenvironment, potentially affecting systemic immune responses (Top panel): fungi, through their metabolic consumption of nutrients, directly influence the growth and metabolic activities of bacterial communities within the gut. This metabolic interaction contributes to the formation of distinct microbial community structures. (Middle panel): Specifically, C. albicans can alter the composition of bacterial populations. The resulting disruption in the microbiome leads to significant changes in the immune microenvironment, affecting the host’s immune responses, including the modulation of inflammatory and anti-inflammatory pathways. (Bottom panel): The metabolites produced by fungi interact with bacterial metabolites to influence immune cell activation. These interactions not only alter the gut microenvironment but can also affect systemic immune functions, potentially influencing host susceptibility to infections and disease progression. Pathways with dashed arrows represent hypothetical interactions yet to be validated in clinical studies (Takeuchi et al., 2024).

Figure 6

The complex interactions between antifungal treatment, cancer immunotherapy, and tumor progression in immunocompromised cancer patients. Cancer therapies, such as chemotherapy and immunotherapy, induce immune suppression, increasing vulnerability to fungal infections. These infections can complicate cancer treatment. Antifungal treatments, like β-glucan, not only help combat fungal infections but also activate immune responses, stimulating T-cells and promoting IFN-γ production. This immune activation can enhance the effectiveness of cancer immunotherapy, particularly anti-PD-L1 therapy. Furthermore, antifungal treatments such as itraconazole influence tumor progression by modulating immune pathways, including the Hedgehog-signaling pathway, which shifts macrophage polarization from the immune-activating M1 phenotype to the immunosuppressive M2 phenotype, supporting tumor growth. Moreover, antifungal treatment can alter the gut microbiota, indirectly influencing systemic immunity and affecting cancer progression. Pathways with dashed arrows represent hypothetical interactions yet to be validated in clinical studies (Jia et al., 2024b; Yang et al., 2022a).