Modulation of the PD-1/PD-L1 axis and tumor immunity by metals and metalloids: mechanistic insights and human health implications.

Immune checkpoints maintain immune homeostasis, but their dysregulation can impair antitumor immunity and promote tumor immune evasion. Accumulating evidence indicates that metals and metalloids are important modulators of immune checkpoint signaling; however, their underlying mechanisms and broader implications for human health have not been systematically synthesized. In this review, we conducted a comprehensive search of PubMed, Web of Science, and Scopus through March 2026 to identify peer-reviewed studies examining metal- and metalloid-associated changes in immune checkpoint expression or function in human, animal, and experimental models. Current evidence suggests that metals and metalloids modulate immune checkpoints in a highly context-dependent manner, with the strongest support for effects on the PD-1/PD-L1 axis, whereas evidence for other checkpoints remains limited. Mechanistically, these effects converge on remodeling of the tumor immune microenvironment, oxidative stress, hypoxia signaling, inflammatory signal transduction, and tumor suppressor and protein homeostasis pathways, thereby influencing T-cell exhaustion, tumor immune evasion, and responses to immune checkpoint inhibitors (ICIs). Emerging clinical evidence further suggests that trace-element status, particularly zinc- and copper-related measures, may have value as candidate biomarkers in immuno-oncology. However, most evidence remains preclinical, and direct human evidence linking metal- and metalloid-associated checkpoint dysregulation to systemic adverse health outcomes or clinically actionable interventions is still limited. Overall, this review connects exposure biology with cancer immunology and identifies metal- and metalloid-associated immune checkpoint modulation as a plausible contributor to altered tumor immunity and a priority for future translational and population-based research.