STAT5-STAT3 Balance Drives Dendritic Cell Immunity

In the relentless pursuit of more effective cancer immunotherapies, recent research has unveiled a groundbreaking mechanism by which the modulation of key transcription factors in dendritic cells can dramatically enhance anti-tumour immunity. A compelling study led by Zhou et al., published in Nature in 2025, reveals how the delicate interplay between STAT3 and STAT5 signaling within dendritic cells (DCs) governs the immune response to tumours, and how targeted degradation of STAT3 using novel small molecules can unleash potent anti-cancer effects.

Dendritic cells are crucial orchestrators of the immune system’s capacity to detect and eliminate malignancies. These highly specialized antigen-presenting cells bridge innate and adaptive immunity by priming CD8⁺ T cells, the immune system’s frontline cytotoxic effector cells. However, tumours often co-opt suppressive molecular pathways to impair DC function, thereby blunting effective anti-tumour T cell responses. STAT3, a transcription factor frequently activated in the tumour microenvironment, has long been implicated in immune evasion through its suppressive influence on dendritic cell activity.

Zhou and colleagues developed an innovative therapeutic approach using SD-36, a highly selective molecule engineered to degrade STAT3 protein within DCs, thus removing this suppressive “brake” on the immune system. Their experiments began with testing SD-36 efficacy in immune-deficient mouse models bearing MC38 colon carcinoma tumours. Notably, low-dose SD-36 treatment failed to inhibit tumour growth in NSG mice, which lack both innate and adaptive immunity, and similarly showed no effect in Rag1-deficient mice that have innate but defective adaptive immunity. These findings underscored the essential role of an intact adaptive immune system for SD-36’s antitumour activity.

To further pinpoint the immune effectors involved, the authors selectively depleted CD8⁺ T cells in wild-type mice bearing tumours and found that SD-36’s anti-tumour efficacy was completely abolished. This pivotal observation confirmed that the therapeutic benefit relied fundamentally on CD8⁺ T cell function. Flow cytometric analyses demonstrated that SD-36 significantly increased the proportion of tumour-infiltrating CD8⁺ T cells expressing critical cytotoxic molecules such as TNF, IFNγ, and granzyme B, across multiple tumour models. This effect delineates a scenario in which STAT3 degradation in DCs indirectly mobilizes a robust cytotoxic T cell response, effectively curtailing tumour progression.

Delving into the mechanistic underpinnings, the study elegantly revealed the role of classical dendritic cells type 1 (cDC1s) in mediating SD-36’s therapeutic effects. In Batf3-deficient mice, which lack cDC1s, SD-36 failed to suppress tumour growth, indicating that these DC subsets are indispensable for the drug’s efficacy. Further dissection using STAT3 knockout mice substantiated that the presence of functional STAT3 in DCs was necessary for SD-36 to exert its anti-tumour activity, as genetic ablation of STAT3 negated the compound’s benefits.

Intriguingly, the authors uncovered a dynamic reprogramming of transcription factor signaling within cDC1s following SD-36 treatment. Phosphorylation levels of STAT3 were markedly diminished, while STAT5 phosphorylation was enhanced—signifying a molecular switch within DCs. This shift was accompanied by upregulation of maturation and co-stimulatory molecules such as MHC class I, MHC class II, and CD80, hallmark indicators of enhanced antigen-presenting capacity and DC activation. The data suggest that STAT3 acts as a negative regulator that suppresses STAT5-driven DC maturation, and that its targeted degradation effectively “releases the brakes” on DC function.

Profound mechanistic clarity was gained through adoptive transfer experiments where wild-type or STAT3-deficient cDC1s were introduced into Batf3-deficient mice. SD-36 restored anti-tumour immunity only when STAT3-competent DCs were present, cementing the conclusion that DC-intrinsic STAT3 degradation is crucial for therapeutic efficacy. Additional genetic validation with STAT5b knockout DCs illustrated that SD-36’s beneficial effects absolutely required functional STAT5 signaling, reinforcing the concept of a STAT3/STAT5 balance that dictates DC phenotype and immune outcomes.

The therapeutic potential of STAT3 degradation was further amplified by combining SD-36 with immune checkpoint blockade (ICB) targeting PD-L1. In highly immunogenic MC38 tumours, anti-PD-L1 therapy alone suppressed tumour growth, whereas in poorly immunogenic B16F10 melanomas, PD-L1 blockade was ineffective. Remarkably, SD-36 monotherapy slowed tumour progression in both models, and the combination with anti-PD-L1 yielded profoundly synergistic inhibition of tumour growth. Complementary ex vivo studies with human ovarian cancer-derived DCs and T cells showed enhanced polyfunctional T cell priming following dual SD-36 and PD-L1 blockade treatment, highlighting translational prospects.

Building upon this foundation, the authors introduced a second-generation STAT3 degrader, SD-2301. Unlike SD-36, which recruits the cereblon–cullin 4A E3 ligase complex for protein degradation, SD-2301 employs a high-affinity VHL ligand to engage the VHL–cullin 2 complex, resulting in significantly improved potency. In vivo experiments revealed that SD-2301 achieved superior STAT3 degradation in DCs and demonstrated greater efficacy in controlling tumour progression at substantially lower doses compared to SD-36.

Functionally, SD-2301 mirrored SD-36 in enhancing effector CD8⁺ T cell populations, with increased expression of IFNγ and granzyme B, alongside upregulation of DC maturation markers within the tumour microenvironment. Crucially, SD-2301 exerted no deleterious effects on tumour vascularization or animal body weight, supporting its safety profile. As with SD-36, SD-2301 synergized robustly with PD-L1 checkpoint blockade to further restrain tumour growth, reinforcing the concept of STAT3 degradation as a powerful adjunct to existing immunotherapies.

Pharmacokinetic profiling of SD-2301 showed favorable attributes including slow clearance and high plasma exposure, critical parameters for clinical translation. High selectivity for STAT3 versus other STAT family members was confirmed in human peripheral blood mononuclear cells, suggesting a minimized risk of off-target effects. These findings collectively underscore the therapeutic promise of targeted STAT3 degradation strategies to reprogram DCs and invigorate anti-tumour immunity.

This seminal work by Zhou et al. thus elegantly illuminates a novel immunotherapeutic paradigm wherein simultaneous inhibition of immunosuppressive STAT3 and activation of stimulatory STAT5 in dendritic cells unleashes potent cytotoxic T cell responses against cancer. The development of highly selective degrader molecules like SD-36 and SD-2301 provides powerful chemical tools to manipulate this axis, opening new avenues for combination therapies with immune checkpoint blockade. The clarity of mechanism, robust preclinical efficacy, and promising translational relevance make this approach a compelling candidate for advancing cancer immunotherapy.

As the field moves forward, targeting transcription factor balance within antigen-presenting cells may become a cornerstone strategy for overcoming tumour immune evasion. By specifically enhancing DC function without globally suppressing STAT3 in all cells, such approaches could minimize collateral immunosuppression and toxicities. The dual effects of STAT3 degradation—releasing immune suppression while promoting DC maturation and T cell priming—may be especially advantageous in “cold” tumours resistant to conventional immunotherapies. Moreover, the synergistic potential with PD-L1 blockade suggests that future clinical regimens could be designed to maximize durable remissions.

In summary, the findings reveal a sophisticated interplay between STAT3 and STAT5 pathways controlling dendritic cell programming that can be harnessed to boost tumour immunity. Utilizing PROTAC technology to selectively degrade STAT3 in DCs represents a leap forward in immuno-oncology, demonstrating that finely tuned modulation of transcriptional networks in immune cells can powerfully reshape anti-cancer immune responses. This study paves the way for a new class of combinatorial therapies that strategically liberate dendritic cells from tumour-induced checkpoints, ultimately empowering the adaptive immune system to achieve sustained tumour control.

Subject of Research: The role of STAT3 and STAT5 transcription factor balance in dendritic cells governing anti-tumour immunity and the therapeutic potential of STAT3 degradation.

Article Title: STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity

Article References:
Zhou, J., Tison, K., Zhou, H. et al. STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity.
Nature (2025). https://doi.org/10.1038/s41586-025-09000-3

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Tags: anti-tumour immunity enhancementcancer immunotherapy mechanismsCD8 T cell activationdendritic cell immunityimmune evasion in tumorsimmunotherapy research advancementsinnovative cancer treatmentssmall molecule therapeutics in cancerSTAT5-STAT3 signaling balancetargeted STAT3 degradationtranscription factors in immune responseZhou et al. Nature study 2025