Psychosocial Determinants of Immunotherapy Response Through Chronic Inflammation and Immune Senescence

Despite revolutionary successes, 60-70% of cancer patients fail to respond to immune checkpoint inhibitors and CAR-T cell therapies, even when tumors harbor predictive biomarkers. We propose "immune biography"—the cumulative encoding of lifetime psychosocial stress in immune system function—as a critical missing variable explaining therapeutic resistance. Chronic stress operates through three neuroendocrine pathways to create dysfunctional T cell states: glucocorticoid receptor signaling programs exhaustion-like transcriptional profiles, chronic inflammation drives bystander T cell dysfunction through IL-6/STAT3/TOX pathways, and catecholamine exposure blocks metabolic reprogramming essential for T cell activation. These stress-programmed T cell phenotypes—measurable through inflammatory markers, exhaustion signatures, and metabolic dysfunction—predict immunotherapy outcomes independently of tumor characteristics. Critically, stress-induced immune dysfunction is modifiable through evidence-based interventions including exercise, β-adrenergic blockade, and IL-6 inhibition. We present immediately actionable strategies for patient stratification and immune enhancement that could improve outcomes by addressing the biological consequences of chronic stress through targeted interventions.