ACKR3 (Atypical Chemokine Receptor 3)

Interestingly, A498-RAD10 cells were cross-resistant to cabozantinib, the tyrosine kinase inhibitor used in first-line treatment of mRCC with nivolumab...In silico data supported a context‑dependent role of PBRM1 in ccRCC patients. To the best of our knowledge, this is the first description of a mechanism of RAD001 and cabozantinib resistance through PBRM1 overexpression and CXCR7/CXCR4 downregulation and suggest new therapeutic perspective for cabozantinib-resistant patients.

Therapeutic strategies include peptide antagonists (BL-8040, Balixafortide), radioligand therapies ([177Lu]Pentixather, [177Lu]Lu-BL02), small-molecule inhibitors (Plerixafor, WK1), and monoclonal antibodies (PF-06747143, Ulocuplomab, LY2624587). Key challenges include off-target uptake due to physiological CXCR4 expression and compensatory signaling via CXCR7. Future directions involve dual-receptor targeting, nanoparticle-based delivery, and integration into precision oncology for both hematologic and solid tumors.

In addition, we propose the clinical potential of CXCL12-CXCR4/CXCR7 axis-related molecules as predictive biomarkers, highlighting the translational value of resistance mechanisms and immune re-sensitization. Through these new perspectives, this review provides an innovative summary and future research directions for understanding the key role of CXCL12 in the liver cancer immune microenvironment and for developing targeted combination immunotherapy strategies.

Furthermore, Meflin deficiency reduced the area of tumor vessels in a TNBC mouse model, highlighting its role in CAF-mediated inhibition of TNBC progression and improvement of drug delivery. Accordingly, Meflin plays a role as a potential functional marker of rCAFs in TNBC.

NTAMPS enables effective prognostic stratification, predicts potential immunotherapy benefit, and highlights therapeutic vulnerabilities. DUXAP8 was further identified as a candidate molecular driver that may improve ESCC management in the context of neoadjuvant therapy.

MIF also engages the mechanistic target of rapamycin complex 1 (mTORC1)/activating transcription factor 4 (ATF4) module to reprogram metabolic processes...The review critically assesses current small-molecule classes targeting the catalytic pocket or trimer/interface to identify design principles for next-generation, receptor-focused modulators suitable for combination therapy. Finally, it proposes an imaging- and flux-based translational approach to select patients, confirm on-target action, and rationally pair MIF-axis blockade with metabolic or immunotherapeutic strategies-aiming to transform correlative data into mechanism-based clinical trials.

Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.

Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.

This approach, first validated in transfected cells by detecting the presence of CXCR4 and ACKR3 homo-oligomers and hetero-oligomers, reveals for the first time endogenous CXCR4 homo-oligomers in non-transfected human leukemia/lymphoma-derived cancer cell lines. More importantly, the investigation in peripheral blood mononuclear cells strongly supports the existence of CXCR4 oligomers in native conditions.

We analyzed pre- and on-treatment biopsies from patients with HR+ breast cancer treated with letrozole to induce estrogen deprivation (ED)...Finally, deletion combined with silencing of the CXCL11 receptors CXCR3 and CXCR7 in MCF7 cells impaired proliferation in response to exogenous CXCL11 and to co-culture with CD8+ T cells in estrogen-free conditions. These findings suggest that CD8+ T cell-associated CXCL11 in the TIME modulates the response of HR+ breast cancer cells to estrogen suppression.

Basal non-chemotactic, cancer cell motility was also suppressed, suggesting a role for ACKR3 in this process. The basal receptor activity in pathophysiology may provide an alternate therapeutic approach for targeting ACKR3.

SIGNIFICANCE STATEMENT: A small molecule inverse agonist of the atypical chemokine receptor 3 (ACKR3), named VUF16840, is characterized in this work. It was shown that VUF16840 was able to inhibit basal as well as ligand-induced ACKR3 activation and, moreover, inhibits the scavenging function of ACKR3.