LILRB4 (Leukocyte Immunoglobulin Like Receptor B4)

P=N/A, N=1, Completed, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Completed | N=10 --> 1

In xenograft MM tumor models in immunodeficient mice, NK cells derived from human peripheral blood and expanded in vitro were combined with BiKE and cGAS-STING signaling agonists, demonstrating effective anti-tumor activity and inhibition of MM cell proliferation. Collectively, the combination of cGAS-STING agonists and LILRB4-targeting NK cell engagers offers a promising approach for treating relapsed/refractory MM.

Notably, silencing LILRB4 not only promoted T cell maturation in spleen and lymph nodes but also enhanced T cell infiltration in tumor tissues. This study offered a highly promising therapeutic strategy for AML and other diseases.

Finally, we showed that LILRB4 regulates CRD-induced mammary tumorigenesis via a non-canonical WNT signaling pathway. These findings identify and implicate LILRB4 as a link between CRD and aggressive mammary tumorigenesis and establish the potential role of the targeted LILRB4a immunotherapy as an inhibitor of CRD-induced lung metastasis.

LILRB4 might functions as a critical regulator of the immunosuppressive TME in GBM by promoting M2 macrophage polarization through the STAT3/IL10 axis. Targeting LILRB4 represents a promising approach for enhancing immunotherapeutic efficacy in GBM.

Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)-naïve CMML. Overall, the data support a future pivotal study of IO-202 + AZA in patients with HMA-naïve CMML. This trial was registered at www.clinicaltrials.gov as #NCT04372433.

P1, N=12, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

Finally, CSN5i-3 effectively disrupted the signaling pathway mediated by Jab1, thereby restoring cellular immune surveillance and halting the progression of AML. Thus, our results highlight the functional role of Jab1 in supporting AML survival and support the development of targeted therapeutic strategies.

Mechanistically, this SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation. These findings define a function for SCG2 in regulating monocytic immunosuppression and suggest that the SCG2-LILRB4 axis might be a therapeutic target.

Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.

These include lenzilumab (anti-GM-CSF) and IO-202 (anti-LILRB4), which have demonstrated promising early efficacy signals but require further study. Established treatments, which include hypomethylating agents and hydroxyurea as well as the JAK1/2 inhibitor ruxolitinib, provide limited survival benefits in CMML, underscoring the urgent need for novel therapeutic development. Coordinated dedicated research efforts have started to evaluate new agents in CMML. Along with further diagnostic and prognostic refinement, these advances are welcomed for this rare and heterogenous disease.

Preclinical or early clinical studies show favorable safety profiles, high tumor specificity, and mechanisms to overcome immune resistance, collectively suggesting the potential for improved patient outcomes and reduced adverse effects. By presenting a comprehensive summary of these advances, this review underscores the translational potential of emerging immunotargets and provides insights to guide the development of innovative therapeutic approaches to improve outcomes for multiple myeloma patients.