Athymic murine models can underestimate the immune-dependent components of chemotherapy efficacy

Athymic mice are widely used in preclinical research to study tumor growth, metastasis, and the efficacy of conventional and targeted therapies. However, these animals are profoundly deficient in thymus-derived conventional T cells while retaining B cells and substantial innate immune function, creating a selective blind spot for treatment effects that require adaptive immune amplification. In addition, many modern chemotherapeutic agents act beyond direct tumor-cell-intrinsic cytotoxicity, relying instead on immunogenic cell death (ICD), antigen presentation, and host immune amplification. An intact immune system is essential for the full therapeutic benefit of these chemotherapy drugs, as agents like anthracyclines and oxaliplatin trigger ICD to recruit and prime T lymphocytes, turning localized tumor damage into systemic, durable protection. Conversely, T-cell deficiency shifts chemotherapy-induced effects toward immunosuppression; in athymic models, the absence of cytotoxic T-cells leaves tumor-associated macrophages and myeloid-derived suppressor cells unchecked, creating an immunosuppressive microenvironment that directly contributes to underestimation of the therapeutic efficacy which is ultimately used in intact immunity. From our perspective, while athymic nude models remain valuable for direct tumor-cell responses and establishing primary human xenografts, but may underestimate endpoints requiring conventional T-cell priming, effector function, checkpoint interactions, systemic tumor control, or immunological memory. We recommend that preclinical study designs adopt a context-appropriate model strategy pairing athymic models with syngeneic or humanized mouse systems to accurately capture the full therapeutic potential of host-dependent anticancer therapies.