SIRPA (Signal Regulatory Protein Alpha)

Finally, we discuss combinatorial strategies integrating TAM reprogramming with CAR T cell therapy or chemotherapy to overcome the immunologically "cold" nature of DMG/DIPG. By uniting mechanistic insights with translational opportunities, this review establishes TAM reprogramming as a critical, underexplored frontier in DMG/DIPG immunotherapy, offering the potential to render an otherwise intractable tumor immunologically targetable.

Systemic administration of anti-SIRPα-cGAMP conjugate significantly inhibited tumor growth in a mouse model of colon adenocarcinoma and improved survival in vivo by simultaneously blocking the CD47-SIRPα "do not eat me" checkpoint and selectively delivering the STING agonist to myeloid cells. These findings suggest that targeted immunostimulatory ADCs may be an effective strategy for overcoming immune resistance in solid tumors.

The hybrid cell-membrane nanovesicles (Fus-CMVs) were constructed by fusing plasma membranes from engineered 293T cells expressing a high-affinity SIRPα variant to block CD47 (Signal A) with membranes from doxorubicin-pretreated 4T1 tumor cells to display CRT (Signal B). In vitro and in vivo studies demonstrated that the "AND" logic-gated Fus-CMVs significantly increased macrophage engulfment of tumor cells and remarkably inhibited tumor growth in different tumor models when compared with single-signal controls. This approach offers a promising approach to enhance macrophage-mediated antitumor immunotherapy.

LM-101 was well tolerated. The preliminary efficacy signal supports further evaluation of LM-101 plus rituximab in relapsed/refractory lymphoma.

Moreover, within the tumor region, the CD47-SIRPα axis facilitated carrier hitchhiking on macrophages, enabling deep penetration into the tumor parenchyma and regulating the tumor microenvironment through the differential recognition of M1/M2-type tumor-associated macrophages. This study presents the first evidence of the dichotomous role of the CD47-SIRPα axis in regulating carrier biocompatibility, offering insights into its function to overcome the tumor permeability barrier challenge.

Mechanistically, the inhibition of CD47 by clofibrate was dependent on PPARα, as evidenced by its reversal upon PPARα silencing. Together, these results uncover a novel mechanism through which clofibrate restricts tumor immune escape by transcriptional suppression of CD47.

Utilizing a newly developed SK-N-AS xenograft model we show effective tumor targeting of the human aGD2-hSIRPα fusion mAbs with hSIRPα in a C-terminal configuration. These data provide the first proof of principal for NB tumor targeted blockade of CD47 by aGD2-hSIRPα fusion mAbs in-vivo and support the further development of aGD2-hSIRPα mAbs as attractive therapeutics to improve aGD2 based NB immunotherapy.

It showed strong diagnostic accuracy for distinguishing LUAD LM from Non-LM or NC, and PBM did not influence the CSF TROP2 level. Collectively, our findings advance the understanding of LUAD-LM pathogenesis and highlight the potential of CSF TROP2 as a diagnostic biomarker for LM.

In conclusion, transfection with siRNA-LNPs resulted in an efficient simultaneous downregulation of phagocytosis checkpoints in human macrophages and augmented macrophage phagocytosis of tumor cells in response to CD47 blockade in vitro. Using siRNA-LNPs in cancer therapy may be a promising potential approach to augment phagocytosis and the innate immune response against tumor growth.

To address this, we developed biomimetic dual-targeting microparticles(MPs)functionalized with anti-PD-L1 and anti-SIRPα nanobodies. This strategy synergized targeted pyroptosis induction with dual immune checkpoint blockade, achieving complete tumor regression, reduced physiological toxicity, and induced a potent effector immune response in murine cancer models, presenting a promising combinatorial approach for lung cancer immunotherapy.

Furthermore, various novel therapeutic strategies-including small-molecule inhibitors, bispecific antibodies, nanoparticle-based agents, and combination therapies-are advancing SIRPα-targeted treatment beyond traditional blockade. These advances move toward precise, synergistic immunotherapy with broad clinical potential.

Computational modeling and screening of tandem constructs revealed an optimal conformation for robust cis-targeting, allowing logic-gated control of ratiometric prophagocytic and antiphagocytic signaling. In situ generation of TrME by delivering mRNA encoding TAA-targeting TrME through an optimized lipid nanoparticle system activates macrophages and induces antitumor responses, significantly inhibiting tumor growth and prolonging survival in multiple solid tumor mouse models.