Mortality and morbidity rates of invasive fungal infections are rising as new pathogens emerge, antifungal resistance rates rise, and susceptible populations increase in numbers. Innovative strategies to identify and characterize novel druggable targets and investigate mechanisms of action driving fungal virulence and survival are urgently needed. For Cryptococcus neoformans, a human fungal pathogen with global distribution and elevated infectivity rates, especially among immunocompromised individuals, elucidation of mechanistic drivers of infection are limited. In this study, we developed an innovative pipeline to explore fluctuations in the fungal infectome combined with phenome fingerprinting to define three categories of putative fungal therapeutic candidates: antifungal, anti-virulence, and infection-relevant. Prioritization of an uncharacterized, conserved, and virulence-associated protein, CipC, explored distinct signatures of extracellular vesicles and pointed towards enhanced antigenic properties. A murine immunization trial revealed limited heightened protection with EVs from a deletion strain of cipC; however, an increased and diversified host immune response was observed, supporting a putative role in pan-fungal immunization. We report a comprehensive pipeline to define and explore novel drivers of fungal infectivity for the identification of new therapeutic targets to improve current treatment and protections strategies against fungal pathogens.