The International Space Station (ISS) presents a complex array of environmental, psychological, social, and technological stressors that challenge human adaptation in orbit. While many of these factors are well documented, this technical note advances a framework of integrated countermeasures tailored to crew size, mission phase, and system contingencies. Drawing from a synthesis of empirical and operational literature, it proposes a layered mitigation model uniting architectural, behavioural, physiological, and automation-based strategies. This multidimensional approach supports adaptive trade-offs between habitat constraints, crew autonomy, and mission control support, promoting sustained performance, safety, and psychosocial resilience in extreme environments. The analysis examines implications for expanding occupant capacity, sustaining extended-duration missions, and informing evidence-based design principles for future orbital and planetary habitats. Findings suggest that, under current operational and environmental limitations, an ISS crew size of six remains optimal; exceeding this threshold demands rigorous, system-wide application of integrated countermeasures. The paper concludes with targeted recommendations, interdisciplinary insights, and open research priorities to guide the evolution of human factors engineering, digital health integration, and adaptive mission design in next-generation space habitats and long-duration exploration missions.