Immunotherapy Heterogeneity in Pulmonary Arterial Hypertension: Cross-Species Determinants and Sex-Stratified Response Mechanisms

Pulmonary arterial hypertension (PAH) exhibits substantial biological heterogeneity that may contribute to variable therapeutic responses and complicate the translation of immunotherapies from experimental models to patients. This Review examines how cross-species variation and biological sex may modify PAH immunotherapeutic responses, with particular attention to differences between target-directed biologics and active immunization. Species-related variation in model fidelity, target conservation, and immune biology, together with sex-associated differences in vascular and immune phenotypes, may contribute to heterogeneous therapeutic responses. These effects may be particularly relevant to active immunization because vaccine efficacy depends on multiple host-dependent immune processes. However, direct evidence for species- and sex-associated differences in PAH vaccine efficacy remains limited, and PAH-specific mechanistic evidence should be distinguished from extrapolation based on broader immunology. We therefore discuss a translational strategy integrating mechanism-guided model selection, cross-species validation, sex-stratified study design, human-relevant experimental systems, and multidimensional analysis to improve the design and interpretation of future PAH immunotherapy studies.