Immune checkpoint blockade, or ICB, has transformed cancer treatment by releasing molecular brakes that restrain T cells. Drugs that block proteins such as PD-1, PD-L1 or CTLA-4 can restore the ability of T cells to recognize and attack malignant cells, producing long-lasting responses in some people with cancer. Yet the treatment does not work uniformly. Its success depends on a chain of events in which tumor antigens are captured, processed and displayed to T cells by antigen-presenting cells, particularly dendritic cells. Among these, conventional type 1 dendritic cells, known as cDC1s, have attracted intense attention because they are highly effective at cross-presenting tumor-derived proteins on major histocompatibility complex class I molecules, a process that activates tumor-killing CD8-positive T cells.

The new work examined whether cDC1s are absolutely required for ICB to eliminate a primary tumor. To do so, the researchers used mice carrying an immunogenic clone of Lewis lung carcinoma, or LLC, a transplantable mouse tumor model. They compared normal animals with genetically modified Batf3-deficient mice. The Batf3 transcription factor is necessary for the development of cDC1s, so Batf3-knockout animals lack this dendritic-cell subset. In normal mice, most animals rejected the LLC tumors after receiving ICB. Surprisingly, the treatment also triggered tumor rejection in 35.7 percent of the Batf3-deficient mice. The result indicates that, at least for this immunogenic LLC tumor, alternative antigen-presenting cells can support an initial antitumor response when cDC1s are absent.

That alternative route appears to involve XCR1-negative antigen-presenting cells. XCR1 is a chemokine receptor associated with cDC1s, making it a useful marker for distinguishing these cells from other antigen-presenting populations. After ICB, the researchers observed increased expression of costimulatory molecules on XCR1-negative APCs in both tumors and draining lymph nodes of Batf3-deficient mice. Costimulatory molecules such as CD40 and CD80 provide essential secondary signals during T-cell activation. Antigen recognition alone is often insufficient; without costimulation, T cells may become inactive or tolerant. The observed increase in CD40 and CD80 suggests that non-cDC1 APCs were not merely present but were being functionally activated in response to checkpoint therapy.

The researchers then investigated why the LLC model could provoke this backup immune pathway while another tumor model, the B16F10 melanoma, remained resistant to ICB. They collected conditioned culture media—the fluid containing molecules secreted by tumor cells—from LLC and B16F10 cultures and exposed bone-marrow-derived dendritic cells to it. Media from LLC cells stimulated both cDC1s and cDC2s, another conventional dendritic-cell subset, causing increased expression of CD40 and CD80. Media from ICB-resistant B16F10 cells did not produce the same effect. This experiment points to soluble factors released by the tumor microenvironment as potential drivers of dendritic-cell activation. The molecules were not identified in the study, but the contrast suggests that tumor cells can differ substantially in their ability to alert and organize immune responses.

To explore that difference at the molecular level, the team performed RNA sequencing on LLC and B16F10 tumor cells. The analysis showed that genes linked to antitumor immunity were more strongly expressed in LLC cells than in B16F10 cells. Such genes could influence how tumor antigens are released, how inflammatory signals are generated or how immune cells are recruited and activated. A tumor that produces the right combination of danger signals may effectively condition multiple APC populations, creating redundancy in the pathway leading to T-cell activation. By contrast, an immune-cold tumor such as B16F10 may fail at several points: it may present fewer recognizable antigens, release weaker activating signals or actively suppress the cells that would otherwise initiate immunity.

The most consequential finding emerged when the researchers tested immune memory. Mice that had become tumor-free after ICB were later exposed again to LLC tumors, a standard rechallenge experiment designed to determine whether the initial response created protective immunological memory. In Batf3-deficient animals that had rejected their primary tumors without cDC1 supplementation, the rechallenged tumors were not spontaneously eliminated. In other words, the mice could mount a successful first attack but did not retain a sufficiently powerful memory response to repel the same tumor a second time. This distinction is biologically important. Primary rejection can rely on a temporary or locally organized immune response, whereas durable memory requires the generation, survival and later reactivation of specialized T-cell populations, processes that depend on precise antigen presentation and coordination among immune cells.

The findings support a two-stage model of checkpoint immunotherapy. During the first stage, activated XCR1-negative APCs, including cDC2-like populations, may present tumor antigens and provide costimulation strong enough to initiate T-cell-mediated destruction. These cells could acquire tumor material in the tumor bed or draining lymph nodes, process it and present it to T cells through major histocompatibility complex molecules. Checkpoint blockade would then remove inhibitory signaling, allowing the newly activated T cells to expand and attack the cancer. During the second stage, however, cDC1s may be indispensable for shaping the quality and persistence of the response. Their specialized cross-presentation capacity could help sustain repeated T-cell stimulation, support the development of memory precursor cells and establish long-term surveillance against residual or returning tumor cells.

The work does not mean that cDC1s are unimportant in all cancers, nor does it show that patients lacking a direct equivalent of the mouse pathway would respond in the same way. The experiments used genetically modified mice and transplantable tumor models, and the percentage of Batf3-deficient animals rejecting LLC was substantially lower than the response seen in wild-type mice. The results instead highlight the complexity of immune responses within tumors and the danger of reducing immunotherapy to a single cellular mechanism. Future treatments may need to activate both cDC1-dependent and cDC1-independent pathways: one to generate a forceful initial attack and another to ensure that the immune system remembers what it has defeated. Identifying the soluble tumor-derived signals that activate alternative APCs could help explain why some cancers respond to ICB while others resist it, while strategies that restore or enhance cDC1 function could improve the durability of responses. The study’s central message is therefore both encouraging and cautionary: the immune system may find more than one way to destroy a tumor, but the route to lasting protection is narrower than the route to an initial victory.

The immune microenvironment surrounding tumors is pivotal in either enabling or thwarting cancer progression. Tumors categorized as ‘cold’ maintain an immunosuppressive atmosphere that limits infiltration by cytotoxic T cells and natural killer (NK) cells, key players in tumor eradication. Conversely, ‘hot’ tumors are characterized by substantial immune cell presence and heightened anti-tumor activity. Central to maintaining the ‘cold’ phenotype are Tregs, a subset of immune cells that suppress excessive immune activation but, paradoxically, can be co-opted by tumors to dampen immune attack. SRC-3, a transcriptional coactivator within Tregs, has emerged as an influential modulator of this immunosuppressive function.

In their early work with mouse models of breast and prostate cancer, the researchers employed genetic ablation techniques to delete SRC-3 specifically in Tregs. This intervention transformed these regulatory cells from tumor protectors into potent tumor antagonists. SRC-3 knockout (KO) Tregs showed an enhanced ability to infiltrate tumors and orchestrate the recruitment of effector immune cells capable of destroying cancer cells. Remarkably, this approach elicited robust tumor eradication without inducing the deleterious side effects commonly associated with conventional immunotherapies, such as autoimmunity or systemic toxicity. Moreover, the SRC-3 KO Tregs appeared to confer durable immunity, preventing tumor recurrence in these mouse models.

At the molecular level, SRC-3 KO Tregs exhibited an altered secretion profile, releasing chemokines that act as chemical beacons to attract cytotoxic CD8+ T cells and NK cells into the tumor milieu. Simultaneously, they impeded immune suppressive cells that would otherwise inhibit this anti-tumor assault. This dual mechanism effectively reshaped the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ ones, thereby facilitating an immune-permissive state conducive to tumor destruction.

Encouraged by these promising outcomes, the research team delved deeper, exploring the applicability of SRC-3-deficient Tregs across a broader spectrum of solid tumors, including glioblastoma, melanoma, and lung cancer. These cancers are notorious for their aggressive progression, resistance to therapy, and poor prognosis, highlighting the urgent need for novel immunotherapeutic strategies.

Glioblastoma, an exceptionally lethal brain cancer, is classically associated with an immune-deserted environment, rendering immunotherapies largely ineffective. In mouse models harboring glioblastoma tumors, those lacking SRC-3 in their Tregs demonstrated a remarkable complete suppression of tumor growth. All control animals succumbed to rapidly progressing tumors by 41 days post-implantation, whereas SRC-3 KO mice survived the entire 52-day study duration without detectable tumor burden. Histological analyses revealed substantial infiltration of cytotoxic T cells within tumor tissues, confirming that SRC-3 ablation in Tregs effectively turns the brain tumor microenvironment from immunologically inert into one actively engaged in anti-tumor warfare.

Melanoma, though somewhat more immunologically active than glioblastoma, also leverages Treg-mediated suppression to evade immune elimination. In this context, SRC-3 KO Tregs conferred significant protection against melanoma development in murine models. While every control mouse developed tumors, an impressive 75% of SRC-3 KO mice remained tumor-free and lived beyond 50 days. The elevated presence of tumor-infiltrating lymphocytes in these subjects underscores the enhanced anti-tumor immunity enabled by the SRC-3 knockout in regulatory T cells.

Lung cancer represents another formidable challenge due to its propensity for rapid progression and immune resistance. Studies revealed that both control mice and those with SRC-3 KO Tregs initially exhibited transient tumor regression. Notably, mice with normal Tregs experienced subsequent tumor resurgence followed by mortality within a month. In contrast, animals harboring SRC-3-deficient Tregs achieved sustained tumor clearance, with 60% surviving long-term and exhibiting no signs of tumor recurrence. This longevity was accompanied by amplified infiltration of immune cells within lung tumor tissues, reiterating the capacity of SRC-3 KO Tregs to remodel the tumor microenvironment favorably.

At the immunological mechanism’s core is the capacity of SRC-3 KO Tregs to proliferate extensively and deploy chemokines that attract and activate effector immune cells while simultaneously inhibiting the recruitment or function of immunosuppressive counterparts. This multifaceted mode of action orchestrates a dynamic shift in the local tumor ecosystem, overriding tumor-induced immune evasion strategies.

These collective experimental findings not only underscore the universality of SRC-3’s role in modulating Treg function across diverse tumor types but also affirm the translational potential of targeting SRC-3 as an innovative cancer immunotherapy approach. By harnessing the intrinsic plasticity of Tregs and reprogramming their activity from tumor-supporting to tumor-fighting, this strategy overcomes significant barriers that have historically limited the efficacy of immunotherapies for solid tumors.

Given these advances, Baylor College of Medicine, in collaboration with CoRegen, Inc., is actively pursuing the commercialization and clinical translation potential of SRC-3-targeted therapies. The intellectual property protecting these discoveries has been licensed to CoRegen, reflecting a commitment to advancing these findings from bench to bedside.

Importantly, the absence of severe immune-related adverse events in these preclinical studies suggests that manipulating SRC-3 in Tregs offers a safer alternative to existing immunomodulatory treatments that often provoke autoimmunity. The promising results also hint at the possibility of durable cancer remission with reduced risk of relapse, a longstanding goal in oncology.

Further research is warranted to unravel the detailed molecular pathways through which SRC-3 governs Treg-mediated immunosuppression and to optimize delivery methods for targeted SRC-3 inhibition in human patients. Additionally, expanding trials to encompass other challenging tumor entities may elucidate the broader applicability of this therapeutic paradigm.

In summation, the innovative manipulation of SRC-3 within Tregs represents a transformative leap forward in cancer immunotherapy. By converting immunosuppressive cells into allies of tumor eradication, this approach promises to reshape the landscape of solid tumor treatment, offering hope for more effective, durable, and side-effect-free therapeutic options in the fight against cancer.

Subject of Research: Animals

Article Title: Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models

News Publication Date: 2-Mar-2026

Web References:

• https://www.pnas.org/doi/10.1073/pnas.2221707120
• https://www.tandfonline.com/doi/full/10.1080/2162402X.2026.2640261#abstract

References:
Han S.J., Lonard D.M., et al. (2026). Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models. OncoImmunology. https://doi.org/10.1080/2162402X.2026.2640261

Image Credits: Baylor College of Medicine

Keywords: cancer immunotherapy, regulatory T cells, SRC-3, tumor microenvironment, glioblastoma, melanoma, lung cancer, immune suppression, solid tumors, chemokines, immune infiltration, immunomodulation