Chemotherapy and male fertility: genotoxic effects on sperm DNA and germ cell integrity

Infertility is a serious concern for young male patients of reproductive age undergoing chemotherapy, which commonly disrupts fertility either temporarily or permanently. Cytotoxic chemotherapeutic agents primarily target rapidly dividing cells; consequently, male germ cells, which undergo continuous proliferation, are particularly vulnerable. These agents can compromise germ cell DNA integrity, thereby adversely affecting sperm quality. Damage to sperm chromatin is associated with reduced motility, increased morphological abnormalities, and decreased fertility potential. With the current success of cancer therapies, life expectancy has significantly improved among cancer patients, and the majority now desire fertility after treatment. Following chemotherapy, many young men require assisted reproductive technologies (ART) to achieve fatherhood. Fertility preservation prior to cancer therapy provides an opportunity for patients to have genetically related offspring, even if their sperm is subsequently damaged by treatment. This review synthesizes current evidence on the genotoxic and epigenetic effects of chemotherapeutic and emerging targeted/immunologic agents on male germ cells and sperm DNA integrity, with particular emphasis on the comparatively underexplored reproductive toxicology of tyrosine kinase inhibitors, immune checkpoint inhibitors, and androgen receptor pathway inhibitors, and outlines current fertility preservation strategies. A comprehensive literature search of PubMed, Scopus, and Web of Science (January 2000–December 2025) was conducted, prioritizing studies from 2010 to 2025.