Signal Regulatory Protein Alpha (SIRPA)

Overview

Signal regulatory protein-α (SIRPα) is a cell-surface inhibitory receptor expressed predominantly on myeloid cells, including macrophages and other phagocytic cells. It is a key component of the CD47-SIRPα axis, an innate immune checkpoint pathway often described as a “don’t eat me” signal. When SIRPα engages CD47 on neighboring cells, downstream inhibitory signaling suppresses phagocytosis and helps regulate immune tolerance and self-recognition.

In cancer biology, this pathway is of major interest because many tumors upregulate CD47 to evade clearance by SIRPα-expressing myeloid cells. As a result, SIRPα has become an important therapeutic target in immuno-oncology, particularly for strategies aimed at restoring macrophage-mediated phagocytosis and enhancing antitumor immunity. Recent studies have explored SIRPα blockade alone and in combination with other therapies, including rituximab, toripalimab, and approaches involving extracellular vesicles, CAR-macrophages, and CD47-directed fusion antibodies.

Recent Publications Summary

Recent publications have focused on SIRPA as part of the CD47–SIRPα innate immune checkpoint axis, with several studies using it to enhance antitumor phagocytosis and immune activation. In preclinical cancer models, transgenic expression of human SIRPα in BALB/c Rag2null/Jak3null mice increased human lymphoma xenograft engraftment by reducing phagocytosis, supporting the utility of SIRPα-humanized immunodeficient mice for xenograft studies 42289615Jun. Related therapeutic work also used SIRPα-based engineering to locally block CD47 signaling, including aGD2-SIRPα fusion antibodies for neuroblastoma that selectively bound tumor cells and mediated CD47 blockade in a GD2-dependent manner 41054394Oct. Similarly, a 3D-printed implantable CAR-macrophage platform incorporated SIRPα-overexpressing extracellular vesicles to mask CD47 on tumor cells, reduce the “don’t eat me” signal, and enhance macrophage-mediated antitumor activity in a post-surgical breast cancer model 41957823Apr.

Other studies evaluated direct SIRPα-targeting immunotherapies. LM-101, an anti-SIRPα antibody, was tested in an open-label phase I trial in patients with relapsed/refractory lymphoma and advanced head and neck cancer, with the stated goal of assessing safety and preliminary antitumor activity as monotherapy and in combination with rituximab or toripalimab 41910591Mar. In multiple myeloma, an oncolytic vaccinia virus encoding a CD47 nanobody was designed to locally block the CD47–SIRPα axis, enhance macrophage phagocytosis, suppress tumor growth, and improve survival in murine models, while also synergizing with bortezomib 41858619Mar. Together, these studies position SIRPA as a therapeutic target for overcoming myeloid immune evasion across several malignancies 41910591Mar41858619Mar41054394Oct.

Beyond oncology, SIRPA has also emerged in disease genetics and immune microenvironment studies. A proteome-wide association study in Alzheimer’s disease identified SIRPA among genes with putative causal relationships to disease risk through cis regulation of plasma protein abundance, with additional support from colocalization and Mendelian randomization analyses 42384774Jul. In metastatic melanoma, SIRPG—not SIRPA—was associated with an exhaustion-prone immune microenvironment, highlighting the broader relevance of the signal regulatory protein family in immune regulation, but not directly implicating SIRPA itself in that study 42167713May.

What Changes, What Holds

1. Humanized SIRPα models strengthen the case that species-matched SIRPα biology can materially alter xenograft behavior
REINFORCES Human SIRPα expression in immunodeficient mice reduced phagocytosis and improved human lymphoma engraftment, which does not revise the baseline CD47–SIRPα checkpoint model but does sharpen an important experimental implication: SIRPα status can be a major determinant of xenograft permissiveness. That makes SIRPα-humanized hosts a more faithful platform for studying human tumor–myeloid interactions, rather than a new biological role for the receptor itself 42289615Jun.

2. Local SIRPα blockade broadens the therapeutic toolkit without changing the core checkpoint story
REINFORCES SIRPα-directed fusion antibodies and related local delivery strategies extend the established use of this axis as an antiphagocytic target in cancer, but they do not displace the baseline account that SIRPα inhibition is being pursued to restore macrophage-mediated clearance. The main update is practical: these approaches aim to concentrate CD47-axis blockade at tumor sites and may reduce systemic exposure, while the phase I antibody study adds early clinical feasibility rather than a new mechanism 41054394Oct41910591Mar.

3. SIRPA is beginning to matter outside oncology, but that role is still separate from the established checkpoint narrative
NEW DIRECTION A proteome-wide genetic association with Alzheimer’s disease points to a possible causal contribution of SIRPA to neurodegenerative risk, which the Overview does not cover and therefore cannot absorb as a contradiction or extension of the cancer checkpoint story. This is hypothesis-generating rather than settled biology, and it sits alongside, not against, the established myeloid inhibitory receptor model; by contrast, the melanoma finding concerns SIRPG, not SIRPA, so it mainly underscores family-level immune relevance 42384774Jul42167713May.

Overview update candidates: humanized SIRPα mouse models as a useful xenograft platform; local/tumor-targeted SIRPα blockade strategies and early clinical testing as practical refinements of the therapeutic approach.