Chemotherapy-Induced Alopecia Beyond Cytotoxicity: Hair Follicle Immune Privilege Collapse and JAK-STAT Signaling

Chemotherapy-induced alopecia (CIA) is a distressing side effect of cancer treatment with limited effective therapeutic options. While CIA has traditionally been attributed to direct p53-mediated cytotoxicity against rapidly proliferating keratinocytes in hair bulbs, emerging evidence suggests a more complex pathogenesis that involves immune-mediated mechanisms analogous to those in alopecia areata (AA). This review synthesizes current literature and proposes that CIA may be fundamentally driven by the collapse of hair follicle (HF) immune privilege (IP). We explore how chemotherapy-induced DNA damage and psychophysiological stress converge to trigger inflammation, characterized by interferon-γ (IFN-γ)-driven pathways, oxidative stress, and neuroimmune dysregulation. We highlight histopathological, genetic, and clinical overlaps between CIA and AA, particularly regarding the shared involvement of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway. Consequently, Janus kinase (JAK) inhibitors (JAKi) are evaluated as potential therapeutic agents for CIA. However, the application of JAKi in oncologic populations requires scrutiny regarding potential immunosuppression and risks of malignancies. Finally, we discuss the context-dependent roles of cytokines involved in the HF-IP collapse pathway, such as interleukin (IL)-15 and IL-1, in HF homeostasis versus inflammation, and we outline future research directions for targeted and safe therapeutic strategies that mitigate CIA without compromising cancer treatment outcomes.