Immune Modulation and Evasion by Cryptococcus spp.: An Integrative Review of Molecular Mechanisms and Experimental Evidence

Abstract

The Cryptococcus species complex are major human pathogenic fungi capable of causing cryptococcosis, a severe pneumonia and meningitidis in both immunocompromised and, in some cases, immunocompetent patients. Their pathogenic success depends not only on classical virulence factors, but also on a coordinated capacity to evade, modulate, and exploit host immune responses across multiple stages of infection. In this review, we synthesize experimental evidence on the principal mechanisms that support cryptococcal immune evasion, integrating findings from molecular, cellular, and host–pathogen interaction studies. We discuss how surface remodeling and capsule organization reduce pathogen-associated molecular pattern exposure and impair immune recognition; how intracellular survival is promoted through phagosomal manipulation, altered trafficking, and nonlytic escape; and how dissemination is facilitated by phenotypic plasticity and flexible strategies for blood–brain barrier traversal. We further examine the contribution of metabolic adaptation, antioxidant defenses, and morphological heterogeneity to fungal persistence under host-imposed stress, as well as the ways in which Cryptococcus interferes with antigen presentation and protective immune polarization. By organizing these mechanisms within a unified framework, this review highlights how immune evasion in Cryptococcus is mediated not by a single determinant, but by an integrated and dynamic network of structural, metabolic, and immunoregulatory processes. A clearer understanding of these interconnected strategies may help refine mechanistic models of cryptococcal pathogenesis and inform future host-directed and antifungal therapeutic approaches.