ABSTRACT Losartan, a widely prescribed antihypertensive agent, has attracted growing interest as a potential adjuvant in cancer therapy due to its affordability, established safety profile and pleiotropic effects. Emerging preclinical evidence demonstrates that losartan can effectively modulate the tumour microenvironment (TME) by inhibiting transforming growth factor‐β (TGF‐β) signalling, reducing stromal stiffness and improving vascular perfusion. These changes are shown to enhance the delivery and efficacy of chemotherapeutic agents, an effect potentially amplified when combined with nanocarriers by augmenting the enhanced permeability and retention effect. Beyond TME remodelling, losartan has demonstrated anti‐tumour activity across various preclinical models, including those of pancreatic, breast and colorectal cancers. Mechanistically, angiotensin II type 1 receptor (AT1R) blockade is reported to modulate key downstream oncogenic pathways, including PI3K/AKT and YAP/TAZ, and to promote vascular normalisation via mechanisms that may include VEGF downregulation, thereby alleviating hypoxia and improving radiotherapy response. Furthermore, evidence suggests losartan remodels the tumour immune landscape by promoting CD8 + T and natural killer (NK) cell infiltration, reprogramming tumour‐associated macrophages (TAMs) and suppressing immunosuppressive cytokines. It also appears to inhibit epithelial‐mesenchymal transition (EMT) and metastasis‐related pathways, including CXCR4/SDF‐1α and matrix metalloproteinases (MMPs). These multifaceted mechanisms highlight its potential as a therapeutic adjuvant capable of overcoming stromal barriers, mitigating immune evasion and limiting metastatic dissemination. However, the translation of these compelling preclinical findings into clinical practice remains a major challenge. The promising preclinical data are tempered by variable efficacy across cancer types, a nascent clinical evidence base and unresolved questions regarding optimal patient selection and dosing. Clinical validation is still nascent, predominantly limited to early‐phase trials and critical parameters such as optimal dosing, treatment sequencing and long‐term safety in oncology patients await rigorous definition. This review synthesises the current mechanistic and translational research on losartan in solid tumours, aiming to clarify its anti‐cancer properties, explore its synergy with nano‐ and immune‐therapeutics, critically assess the associated challenges and identify key gaps and future directions for clinical application. Trial Registration: ClinicalTrials.gov identifier: NCT01821729 and NCT03563248
Wang et al. (Thu,) studied this question.