Commentary on “Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors”

Abstract

Tumor-associated macrophages (TAMs), long exploited by cancers to evade immune detection, can now be reprogrammed into potent antitumor effectors through cutting-edge viral engineering. In a landmark study published in the Journal for Immunotherapy of Cancer, Zhang et al introduced an innovative adenovirus, Adv-mSS, that blocks two critical “don’t eat me” signals, CD47 and CD24, used by tumors to paralyze macrophage activity. By converting immunosuppressive TAMs into tumor-engulfing predators and reigniting CD8 T-cell response, Adv-mSS eradicated tumors across multiple preclinical models. This strategy offers a promising avenue for activating both innate and adaptive immunity against cancer and may address key limitations of current immunotherapies.

Immunotherapy has transformed oncology, exemplified by checkpoint inhibitors targeting Programmed Death 1 (PD-1)/Programmed Death Ligand 1 (PD-L1) and cytotoxic T Lymphocyte-Associated Protein 4 (CTLA-4) in melanoma and lung cancer. However, their limited efficacy in other solid tumors underscores the need for strategies that engage innate and adaptive immunity. Tumor-associated macrophages (TAMs), abundant in many malignancies, are pivotal regulators of antitumor immunity due to their phagocytic activity, capacity to remodel the tumor microenvironment, and ability to prime CD8+T cells.¹ Recent preclinical and clinical studies emphasize TAMs as therapeutic targets, given their dual role in promoting immunosuppression or antitumor activity, depending on polarization. Zhang et al have now engineered an adenovirus (Adv-mSS) that enhances TAM phagocytosis by dual targeting of the CD47 and CD24 receptors, offering a novel approach to amplify antitumor immunity.

Phagocytosis is regulated by a delicate balance between “eat-me” and “don’t eat-me” signals exploited by cancer cells to evade immune detection. Among these, CD47 and CD24 have emerged as critical mediators of immune evasion. CD47 is a ubiquitously expressed protein that binds to signal regulatory protein alpha (SIRPα) on macrophages, effectively inhibiting phagocytosis.² Furthermore, elevated CD47 levels correlate with poor prognosis across cancers.³ In clinical trials, targeting CD47 showed promising results in a phase Ib/II trial in combination with cetuximab in Kirsten Rat Sarcoma Virus (KRAS) wild-type colorectal cancers.⁴ However, systemic CD47 blockade risks anemia due to its expression on red blood cells. Similarly, CD24 interacts with macrophage Siglec-10 to suppress phagocytosis, and preclinical studies highlight its potential as a therapeutic target. Targeting this axis has also demonstrated potential in preclinical studies as well.⁵ Despite these advances, single target approaches often fail due to redundant signaling pathways. To address this, Zhang et al designed Adv-mSS, an oncolytic adenovirus encoding soluble decoys for SIRPα and Siglec-10.⁶ SIRPα and Siglec-10 are two surface proteins expressed by macrophages that interact respectively with the “don’t eat me” receptors CD47 and CD24 on cancer cells. These decoys competitively bind CD47 and CD24 on tumor cells, masking inhibitory signals and restoring macrophage phagocytic activity.

In vitro experiments demonstrated that Adv-mSS-infected tumor cells secrete decoys that block CD47 and CD24, enhancing macrophage phagocytosis and tumor necrosis factor-α (TNF-α) production compared with non-engineered adenoviruses or single-target variants. In vivo, Adv-mSS inhibited tumor growth across lung, hepatocellular, and colorectal cancer models. Mechanistically, Adv-mSS polarized TAMs toward a pro-inflammatory phenotype marked by upregulated CD86, Interferon Gamma (IFNγ), TNFα, and inducuble Nitric Oxide Synthase (iNOS). Concurrently, CD8+T cell infiltration and activation increased significantly. Crucially, the therapeutic efficacy of Adv-mSS depended on both TAMs and CD8+T cells, underscoring the necessity of innate-adaptive immune synergy. The study further revealed that TAMs from Adv-mSS-treated hepatocellular carcinoma models stimulated the proliferation of antigen-specific OT-1 T cells.⁶ While the high immunogenicity of ovalbumin may have amplified this effect, the findings highlight the potential of Adv-mSS to enhance antigen presentation, a critical step for systemic immunity. No such evidence was provided for the other oncolytic viruses (OVs) targeting CD47^{7 8} or both CD47 and CD24,⁹ where no specific depletion of CD8 T cells was performed.

Robust and sustained immune response against cancer will profit from the involvement of both adaptive and innate immunity. The activation of adaptive immunity would imply that cancer cells harboring the same antigens in other locations could be recognized by T cells. A key limitation of current oncolytic virus therapies is their reliance on intratumoral injection due to the short systemic half-life.¹⁰ This approach is inconvenient for patients with metastatic cancer. It can be inferred that Adv-mSS may circumvent this hurdle by inducing robust CD8+T cell responses capable of generating an abscopal effect. Consequently, the immune response initiated by Adv-mSS may not solely concentrate on the primary tumor but also bolster the body’s ability to recognize and annihilate metastatic tumors that are distant from the injection site. Supporting this, Adv-huSS, a recombinant oncolytic adenovirus engineered to express the human extracellular domains of SIRPα and Siglec-10, demonstrated significant tumor growth inhibition in a humanized hepatocellular carcinoma model.⁶ This pivotal result underscores the translational potential of the innovative approach developed by Zhang et al, bridging the preclinical findings to possible clinical applications in treating advanced cancers.

OVs represent a novel class of cancer therapeutics, leveraging their ability to selectively infect and lyse cancer cells while simultaneously stimulating antitumor immunity. By inducing immunogenic cell death and releasing tumor antigens, OVs create an inflammatory microenvironment conducive to immune activation. Approved agents like talimogene laherparepvec for melanoma highlight the clinical viability of this approach. Cutting-edge advances in OV engineering now enable the strategic incorporation of diverse immunomodulatory payloads, including cytokines (eg, Granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin 12 (IL-12)), co-stimulatory molecules (eg, CD40L), antibody-based agents targeting immune checkpoints (anti-CD47, anti-SIRPα) and inhibitory receptors (anti-Siglec-10), further enhancing their therapeutic potential. Adv-mSS elevates this paradigm by secreting soluble SIRPα and Siglec-10 decoys, effectively “unmasking” tumor cells. Unlike single-target OVs (eg, anti-CD47), Adv-mSS pre-empts resistance, integrating innate and adaptive immune activation, offering a more robust therapeutic strategy.

In conclusion, Zhang et al demonstrate that dual CD47/CD24 blockade via Adv-mSS synergizes innate and adaptive immunity, surpassing single-target approaches. Validated across multiple preclinical models, this strategy underscored the potential translational significance of this recombinant adenovirus. The work of Zhang et al represents a significant advance in cancer immunotherapy, providing a novel tool to harness the synergistic power of TAMs and CD8 T cells (figure 1). By simultaneously targeting two “don’t eat me” pathways, Adv-mSS offers a promising strategy to overcome tumor immune evasion and induce a robust and systemic antitumor response. Adv-mSS addresses key resistance mechanisms that limit the efficacy of current immunotherapies by engaging innate and adaptive immunity.

Figure 1. Impact of Adv-mSS on cancer immunity. (1) Adv-mSS infects cancer cells and induces the secretion of the extracellular domains of SIRPα and Siglec-10. (2) These domains act as decoys, binding to CD47 and CD24 on cancer cells and effectively masking these inhibitory signals from macrophages, thereby increasing phagocytic activity of macrophages against cancer cells. (3) Macrophages can present engulfed neoantigens (here ovalbumin) through MHC I to CD8 T cells. (4) Activated CD8 T cells induce anticancer immunity by releasing cytotoxic granules such as granzyme B. SIRPα: signal regulatory protein alpha, TCR: T Cell Receptor, MHC: Major Histocompatibility Complex.