Fungal infections caused by Candida species have become a constant threat to public health, especially for immunocompromised patients, who are considered susceptible to this type of opportunistic infections. Candida albicans is known as the most common etiological agent of candidiasis; however, other species, such as Candida tropicalis, Candida parapsilosis, Nakaseomyces glabrata (previously known as Candida glabrata), Candida auris, Candida guilliermondii, and Pichia kudriavzevii (previously named as Candida krusei), have also gained great importance in recent years. The increasing frequency of the isolation of this non-albicans Candida species is associated with different factors, such as constant exposure to antifungal drugs, the use of catheters in hospitalized patients, cancer, age, and geographic distribution. The main concerns for the control of these pathogens include their ability to evade the mechanisms of action of different drugs, thus developing resistance to antifungal drugs, and it has also been shown that some of these species also manage to evade the host’s immunity. These biological traits make candidiasis treatment a challenging task. In this review manuscript, a detailed update of the recent literature on the six most relevant non-albicans Candida species is provided, focusing on the immune response, evasion mechanisms, and new plant-derived compounds with antifungal properties.

Pathogenic fungi that exhibit the ability to alternate between hyphal and yeast morphology in response to environmental stimuli are considered dimorphic. Under saprobic conditions, some fungi exist as filamentous hyphae, producing conidia. When conidia are inhaled by mammals or traumatically inoculated, body temperature (37 °C) triggers dimorphism into yeast cells. This shift promotes fungal dissemination and immune evasion. Some fungal pathogens undergo dimorphism in the contrary way, forming pseudohyphae and hyphae within the host. While temperature is a major driver of dimorphism, other factors, including CO₂ concentration, pH, nitrogen sources, and quorum-sensing molecules, also contribute to morphological shifts. This morphological transition is associated with increased expression of virulence factors that aid in adhesion, colonization, and immune evasion. Candida albicans is a fungus that is commonly found as a commensal on human mucous membranes but has the potential to be an opportunistic fungal pathogen of immunocompromised patients. C. albicans exhibits a dimorphic change from the yeast form to the hyphal form when it becomes established as a pathogen. In contrast, Histoplasma capsulatum is an environmental dimorphic fungus where human infection begins when conidia or hyphal fragments of the fungus are inhaled into the alveoli, where the dimorphic change to yeast occurs, this being the morphology associated with its pathogenic phase. This review examines the main signaling pathways that have been mostly related to fungal dimorphism, using as a basis the information available in the literature on H. capsulatum and C. albicans because these fungi have been widely studied for the morphological transition from hypha to yeast and from yeast to hypha, respectively. In addition, we have included the reported findings of these signaling pathways associated with the dimorphism of other pathogenic fungi, such as Paracoccidioides brasiliensis, Sporothrix schenckii, Cryptococcus neoformans, and Blastomyces dermatitis. Understanding these pathways is essential for advancing therapeutic approaches against systemic fungal infections.

Pathogenic fungi exhibit morphological plasticity, a phenomenon known as dimorphism, which allows them to switch between yeast and hyphal forms in response to environmental stimuli. Thermodimorphic fungi undergo this transition based on temperature changes, playing a crucial role in their virulence and life cycle. Under saprobic conditions, some fungi exist as filamentous hyphae, producing conidia. When conidia are inhaled by mammals or traumatically inoculated body temperature (37°C) triggers their dimorphism into yeast cells. This shift promotes fungal dis-semination and immune evasion. Some fungal pathogens undergo dimorphism in the contrary way, forming pseudohyphae and hyphae within the host. While temperature is a major driver of di-morphism, other factors, including CO₂ concentration, pH, nitrogen sources, and quorum-sensing molecules, also contribute to morphological shifts. This morphological transition is associated with increased expression of virulence factors that aid in adhesion, colonization, and immune evasion. This review examines the signaling pathways regulating fungal dimorphism, focusing on H. cap-sulatum as a model for mycelium-to-yeast transitions and C. albicans for yeast-to-hypha transitions. Understanding these pathways is essential for advancing therapeutic approaches against systemic fungal infections.

Mammalian models, such as murine, are used widely in pathophysiological studies because they have a high degree of similarity in body temperature, metabolism, and immune response with humans. However, non-vertebrate animal models have emerged as alternative models to study the host-pathogen interaction with minimal ethical concerns. Galleria mellonella is an alternative model that has proved useful in studying the interaction of the host with either bacteria or fungi, performing drug testing, and assessing the immunological response to different microorganisms. The G. mellonella immune response includes cellular and humoral components with structural and functional similarities to the immune effectors found in higher vertebrates, such as humans. An important humoral effector stimulated during infections is apolipophorin III (apoLp-III), an opsonin characterized by its lipid and carbohydrate-binding properties that participate in lipid transport, as well as immunomodulatory activity. Despite some parameters, such as the measurement of phenoloxidase activity, melanin production, hemocytes counting, and expression of antimicrobial peptides genes are already used to assess the G. mellonella immune response to pathogens with different virulence degrees, the apoLp-III quantification remains to be a parameter to assess the immune response in this invertebrate. Here, we propose an immunological tool based on an enzyme-linked immunosorbent assay that allows apoLp-III quantification in the hemolymph of larvae challenged with pathogenic agents. We tested the system with hemolymph coming from larvae infected with Escherichia coli, Candida albicans, Sporothrix schenckii, Sporothrix globosa, and Sporothrix brasiliensis. The results revealed significantly higher concentrations of apoLp-III when each microbial species was inoculated, in comparison with untouched larvae, or inoculated with phosphate-buffered saline. We also demonstrated that the apoLp-III levels correlated with the strains’ virulence, which was already reported. To our knowledge, this is one of the first attempts to quantify apoLp-III, using a quick and easy-to-use serological technique.

Non-albicans Candida (NAC) species have emerged as clinically important opportunistic pathogens with distinct ecological, physiological, and pathogenic traits. Successful colonization and infection require these yeasts to survive within heterogeneous and continuously changing host microenvironments, where they encounter multiple and often simultaneous challenges. This review comparatively examines the adaptive responses of Nakaseomyces glabratus, Candida parapsilosis, Candida tropicalis, Candida auris, and Pichia kudriavzevii to major host-derived pressures, including thermal stress, nutrient restriction, fluctuations in oxygen availability and pH, and oxidative and nitrosative stress. Although exposed to similar environmental constraints, these species differ in how they integrate responses involving metabolic reprogramming, stress response mechanisms, cellular homeostasis, and structural modifications. Particular attention is given to cell wall remodeling as a dynamic interface linking environmental adaptation with adhesion, biofilm formation, immune recognition, and antifungal susceptibility. We further discuss how sustained adaptive responses may contribute to persistence and antifungal tolerance, thereby promoting fungal survival and complicating therapeutic eradication. Collectively, the pathogenic success of NAC species extends beyond classical virulence factors and depends on their capacity to dynamically adjust their physiology to host-imposed constraints, with both shared and species-specific strategies ultimately favoring survival and persistence during infection across diverse host niches under conditions of sustained therapeutic pressure.

Non-albicans Candida (NAC) species have emerged as clinically important opportunistic pathogens with distinct ecological, physiological, and pathogenic traits. Successful colonization and infection require these yeasts to survive within heterogeneous and continuously changing host microenvironments, where they encounter multiple and often simultaneous challenges. This review comparatively examines the adaptive responses of Nakaseomyces glabratus, Candida parapsilosis, Candida tropicalis, Candida auris, and Pichia kudriavzevii to major host-derived pressures, including thermal stress, nutrient restriction, fluctuations in oxygen availability and pH, and oxidative and nitrosative stress. Although exposed to similar environmental constraints, these species differ in how they integrate responses involving metabolic reprogramming, stress response mechanisms, cellular homeostasis, and structural modifications. Particular attention is given to cell wall remodeling as a dynamic interface linking environmental adaptation with adhesion, biofilm formation, immune recognition, and antifungal susceptibility. We further discuss how sustained adaptive responses may contribute to persistence and antifungal tolerance, thereby promoting fungal survival and complicating therapeutic eradication. Collectively, the pathogenic success of NAC species extends beyond classical virulence factors and depends on their capacity to dynamically adjust their physiology to host-imposed constraints, with both shared and species-specific strategies ultimately favoring survival and persistence during infection across diverse host niches under conditions of sustained therapeutic pressure.