The PI3K signaling pathway is critical for numerous cellular functions, including growth, survival, and metabolism. Dysregulation and hyperactivation of this pathway, often through mutations or overexpression, are common in many cancers, including breast tumors. Among the Class I PI3K isoforms, p110δ has traditionally been associated with hematological malignancies and immune cell function. However, emerging evidence has suggested a more nuanced role for p110δ in solid tumors, such as breast cancer. The study led by Goulielmaki and colleagues delves deeply into this less explored territory, revealing that targeting p110δ with IOA-244 can effectively disrupt tumor cell survival and proliferation mechanisms.

The research hinges on the molecular specificity of IOA-244, which distinguishes it from other PI3K inhibitors by exhibiting a profound selectivity for the p110δ isoform. Previous pan-PI3K inhibitors often suffered from off-target effects and dose-limiting toxicities due to the inhibition of multiple PI3K isoforms involved in normal physiological processes. IOA-244’s precision promises a better therapeutic window, minimizing side effects while maximizing antitumor activity. Mechanistic studies demonstrated that upon administration, IOA-244 effectively blocks p110δ-mediated signaling cascades, leading to apoptosis and autophagy in breast cancer cells—salient processes that undermine tumor viability.

In vitro studies revealed that breast cancer cell lines treated with IOA-244 experienced significant growth inhibition. The inhibitor was shown to selectively impair the phosphorylation of downstream effectors such as AKT and mTOR, key nodes in the PI3K signaling pathway responsible for cell cycle progression and survival. These biochemical hallmarks corroborate the hypothesis that p110δ plays a previously underappreciated role in sustaining breast cancer cell growth and that its inhibition with IOA-244 cripples the tumor cells’ proliferative capacity.

Moving beyond cell culture, the team evaluated IOA-244 in vivo using murine models harboring human breast tumor xenografts. Treatment with the inhibitor resulted in a pronounced reduction in tumor volume compared to untreated controls. Notably, IOA-244 exhibited robust anti-tumor activity without eliciting overt toxicity, affirming its safety profile. The authors stressed that this aspect of the drug is especially vital since long-term tolerability is a crucial concern when developing therapies intended for sustained use in chronic cancer management.

An intriguing facet of this study is the dual utility of IOA-244—not only as a monotherapy but also in synergy with established therapeutic agents such as chemotherapy and immune checkpoint inhibitors. Combination regimens enhanced the therapeutic efficacy markedly, underscoring the potential of IOA-244 to integrate seamlessly into existing treatment paradigms. The co-administration of IOA-244 alongside immune modulators appeared to amplify antitumor immunity, possibly through modulation of the tumor microenvironment, which is often immunosuppressive in breast cancers.

Moreover, molecular profiling of treated tumors exhibited a decrease in regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), both of which contribute to immune evasion and cancer progression. IOA-244’s ability to recalibrate the immune milieu offers a compelling rationale for its combination with immunotherapies that rely on reactivating the patient’s immune response against cancer cells. This property could be particularly transformative for patients with tumors that are refractory to conventional treatments or those exhibiting resistance to immune checkpoint blockade.

The research team employed advanced transcriptomic and proteomic approaches to dissect the broader impact of IOA-244 on tumor biology. They identified that IOA-244 treatment downregulated genes involved in cell adhesion and metastasis pathways, potentially curtailing the invasive and metastatic potential of breast cancer cells. This multi-pronged assault on tumor progression reaffirms IOA-244 as a formidable candidate in the oncologist’s arsenal, not just for tumor eradication but also for preventing disease dissemination and relapse.

A particularly compelling insight from the study is the inhibitor’s impact on cancer stem cell populations within breast tumors. These cells are notorious for their role in therapy resistance and tumor recurrence. IOA-244 diminished markers associated with stemness and self-renewal, implying that it might effectively target the ‘root’ of tumor persistence. Targeting these resilient cell populations could improve long-term outcomes and reduce relapse rates, a significant hurdle in breast cancer therapeutics.

The specificity of IOA-244 also paves the way for biomarker-driven patient selection. Identifying patients whose tumors demonstrate p110δ dependency or overexpression could refine treatment protocols, ensuring maximum benefit from IOA-244 while sparing others from ineffective therapy. Biomarker development is pivotal in ushering personalized medicine approaches in oncology, where treatments are tailored to individual tumor profiles.

While this study lays a solid preclinical foundation, the translation of IOA-244 into clinical settings remains an exciting and anticipated next step. Phase I trials are warranted to assess pharmacokinetics, optimal dosing, and initial efficacy in humans. Given the favorable safety and potent antitumoral effects observed in preclinical models, IOA-244 is well poised to progress through clinical development swiftly.

The significance of this advancement cannot be overstated. Breast cancer treatment has largely revolved around estrogen receptor targeting, HER2 inhibition, and cytotoxic chemotherapy. However, many patients eventually develop resistance or suffer from side effects, underscoring the urgent need for novel, more targeted agents. IOA-244 promises to fill this therapeutic void by attacking a hitherto underexploited pathway that plays a critical role in tumor survival.

Furthermore, the versatility of IOA-244 in combination therapies heralds a broader application spectrum that may extend beyond breast cancer. Given the involvement of PI3K signaling in diverse tumor types, this inhibitor’s platform could be adapted or combined with other agents for multifactorial attack strategies in oncology.

In summary, the study by Goulielmaki et al. has brought IOA-244 from conceptualization to compelling proof-of-concept validation, illustrating that selective p110δ inhibition is a viable and potent strategy to curb breast tumor progression. Its dual capability to act alone or synergistically offers oncologists a flexible, precision medicine tool against an often intractable disease. This research invites a paradigm shift, advocating for deep dives into isoform-specific targeting within the PI3K pathway as a cornerstone for next-generation cancer therapies.

As breast cancer continues to challenge medical science with its heterogeneity and adaptive resistance, IOA-244 shines as a beacon of hope that holds the potential to transform patient outcomes through precision molecular intervention. The oncology community eagerly anticipates further clinical insights into this promising compound, which could soon redefine the standards of breast cancer treatment in the years ahead.

Subject of Research: Targeting the p110δ isoform of PI3K in breast cancer using the novel inhibitor IOA-244

Article Title: IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy

Article References:
Goulielmaki, E., Tsapara, A., Xenou, L. et al. IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03073-3

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-026-03073-3

The estrogen receptor has long been recognized as a critical driver of breast cancer proliferation in ER+ tumors. Conventional therapies primarily rely on endocrine treatment strategies that either block the receptor’s activity or reduce estrogen production. However, resistance mechanisms frequently emerge, rendering these treatments less effective over time and leading to disease progression. The new therapeutic paradigm investigated in this phase 1 trial focuses not merely on inhibiting the receptor but on actively degrading it, thereby offering the potential to overcome resistance and achieve more sustained tumor suppression.

At the core of this study lies a class of compounds known as selective estrogen receptor degraders (SERDs). These molecules operate by binding to the estrogen receptor and promoting its degradation via the ubiquitin-proteasome system, effectively eliminating the receptor from cancer cells. This process halts the aberrant signaling cascade that fuels tumor growth. While previous generations of SERDs have shown clinical promise, issues such as suboptimal bioavailability and adverse side effects have limited their widespread use. The investigational drug assessed in this trial represents a significant refinement, demonstrating improved pharmacokinetics and tolerability.

The phase 1 trial enrolled patients with advanced or metastatic ER+/HER2– breast cancer who had exhausted standard treatment options. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of the novel ER degrader. Patients received escalating doses of the compound, monitored closely for adverse effects, and underwent comprehensive biomarker analyses to elucidate the drug’s mechanism of action and impact on tumor biology.

Encouragingly, the investigational agent exhibited a favorable safety profile, with most adverse events being mild to moderate and manageable. Importantly, no dose-limiting toxicities emerged during the study, allowing for the identification of an optimal dosing regimen. Pharmacokinetic data revealed that the drug achieved therapeutic plasma concentrations rapidly and maintained them with once-daily oral administration, a noteworthy advantage over previous SERDs requiring more complex dosing strategies.

Preliminary efficacy signals were equally promising, with several patients exhibiting partial responses or stable disease lasting multiple months. These early tumor responses, observed even in heavily pretreated populations, underscore the potential of ER degradation as a viable strategy to circumvent resistance to classical endocrine therapies. Moreover, biomarker assessments confirmed robust downregulation of estrogen receptor expression and suppression of downstream signaling pathways, validating the intended mechanism of therapeutic action.

The implications of these findings resonate strongly within the oncology community. By advancing beyond receptor blockade to receptor elimination, this therapy could redefine the clinical management of ER+ breast cancer, particularly for patients with metastatic disease who face limited options. Although this phase 1 study primarily addresses safety and early efficacy, its results lay the groundwork for larger, randomized trials to establish definitive clinical benefit and elucidate long-term outcomes.

One of the notable scientific achievements of this trial is the integration of cutting-edge molecular diagnostic techniques. High-throughput sequencing, circulating tumor DNA analysis, and advanced imaging modalities were employed to monitor treatment response in real-time and identify molecular correlates of efficacy and resistance. These comprehensive datasets enrich our understanding of tumor heterogeneity and adaptive mechanisms, potentially guiding personalized treatment strategies in the future.

Furthermore, the study’s design exemplifies the growing trend toward precision oncology, wherein therapies are tailored based on individual tumor biology rather than a one-size-fits-all approach. The selective degradation of estrogen receptors targets a fundamental vulnerability specific to ER+ cancers, sparing non-tumor tissues and minimizing systemic toxicity, thereby enhancing the therapeutic window.

The successful implementation of selective ER degradation also stimulates a broader reevaluation of receptor-targeted therapies across cancer types. By harnessing the cell’s own protein degradation machinery, similar strategies could be adapted to target other oncogenic receptors that have historically been challenging to inhibit effectively. This trial thus serves as a proof-of-concept not only for breast cancer treatment but as a beacon for drug development in oncology at large.

While the current findings generate significant optimism, several questions remain to be addressed. The durability of clinical responses, optimal sequencing with other therapeutic modalities, and potential resistance pathways to ER degraders warrant comprehensive investigation. Additionally, identifying predictive biomarkers to select patients most likely to benefit will be crucial for maximizing clinical impact.

Collaboration among academic institutions, pharmaceutical industry partners, and regulatory agencies will be vital to accelerate the development and approval of this promising therapeutic class. The speed and rigor with which this early-phase trial was conducted exemplify the collaborative spirit essential to translating bench science into transformative clinical solutions.

In summary, the phase 1 trial led by Hamilton, Layman, Cosgrove, and colleagues represents a milestone in breast cancer research by demonstrating the feasibility, safety, and preliminary efficacy of ER degradation in advanced ER+/HER2– breast cancer. This novel approach could ultimately reshape treatment paradigms, offering hope to patients confronted with aggressive disease and limited therapeutic options. As the oncology field eagerly anticipates forthcoming phase 2 and 3 studies, the potential to improve survival and quality of life for millions of patients worldwide shines brighter than ever.

The journey from conceptual innovation to clinical application continues, propelled by relentless scientific inquiry and patient-centered research. Selective estrogen receptor degradation stands poised to become an integral weapon in the arsenal against breast cancer, transforming outcomes and exemplifying the power of targeted molecular therapy.

Subject of Research:
Advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2–) breast cancer treatment through selective estrogen receptor degradation.

Article Title:
ER degradation for ER⁺/HER2– advanced or metastatic breast cancer: a phase 1 trial.

Article References:
Hamilton, E., Layman, R.M., Cosgrove, D. et al. ER degradation for ER⁺/HER2– advanced or metastatic breast cancer: a phase 1 trial. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67485-y

Image Credits: AI Generated

ER-positive breast cancer represents a significant subset of breast cancer diagnoses globally, distinguished by its reliance on estrogen receptor signaling to drive tumor growth and survival. Despite advances in endocrine therapies, resistance mechanisms inevitably emerge, leading to therapeutic failure and disease progression. This new research identifies a previously underappreciated link between ESR1 activity and autophagy—a catabolic process essential for maintaining cellular homeostasis and stress tolerance—demonstrating that ESR1 exerts a suppressive control over p62/SQSTM1-dependent autophagy pathways in these tumor cells.

The autophagy receptor protein p62/SQSTM1 serves as a nodal regulator for selective autophagy, facilitating the degradation of ubiquitinated proteins and damaged organelles. Importantly, p62 is known to influence oxidative stress responses by mediating the turnover of pro-oxidant proteins and promoting cellular adaptation to stress. The study illuminates how suppression of ESR1 augments p62 expression and functionality, leading to a resurgence of autophagic flux. This process heightens cellular cleanses of oxidative damage and misfolded proteins, thereby sensitizing cancer cells to exogenous challenges such as reactive oxygen species and ionizing radiation.

Methodologically, the team employed an integrative approach combining molecular genetic techniques, cellular assays, and in vivo models to dissect the ESR1-p62 autophagy axis. By knockdown or pharmacological inhibition of ESR1, researchers observed restored autophagic activity in ER-positive breast cancer cell lines, accompanied by increased vulnerability to oxidative stress and radiotherapy-induced cytotoxicity. Conversely, enforced ESR1 expression attenuated autophagy, underscoring the receptor’s suppressive role in these pathways.

From a therapeutic perspective, this discovery unveils ESR1 as a dual-function target—beyond its canonical transcriptional regulation of proliferative genes, its modulation appears pivotal in orchestrating autophagy-mediated stress responses. This insight challenges established dogma, suggesting that endocrine therapies could be optimized or combined with autophagy-modulating agents to overcome resistant phenotypes and enhance treatment efficacy. Such combination strategies could achieve higher rates of tumor cell eradication by synergistically impairing adaptive survival mechanisms.

The intricate interplay between ESR1 signaling and autophagy impacts how ER-positive breast cancer cells navigate oxidative onslaughts, a situation commonly encountered during radiation therapy. Radiation generates high levels of reactive oxygen species (ROS), which induce DNA damage and cellular apoptosis; however, cancer cells frequently deploy autophagy to mitigate these insults, fostering radiotherapy resistance. By reinstating p62-dependent autophagy, ESR1 inhibition disrupts this protective shield, rendering cancer cells more susceptible to ROS-mediated apoptosis and improving overall treatment outcomes.

Additionally, the results elucidate the molecular cascades downstream of ESR1 that converge on autophagic machinery, including the modulation of key autophagy-related genes and signal transduction pathways. The study highlights the complex regulatory network where estrogen receptor influences autophagy markers such as LC3 and ATG proteins through transcriptional and post-translational mechanisms, aligning cellular catabolic processes with hormone receptor status and environmental stressors.

Importantly, the translational potential of this work extends to the clinical realm. The findings advocate for the development of next-generation ESR1 inhibitors with enhanced specificity for autophagy pathway restoration. Moreover, biomarkers related to p62/SQSTM1 expression and autophagic flux could serve as predictive tools for identifying patients likely to benefit from combined endocrine and autophagy-targeted therapies, paving the way for precision oncology approaches.

This paradigm-shifting research also prompts reevaluation of current therapeutic algorithms by integrating autophagy modulation as a cornerstone in managing ER-positive breast cancer. It calls attention to the balance between endocrine resistance mechanisms and cellular quality control systems, suggesting a synergistic vulnerability that could be tactically exploited. The prospect of overcoming radioresistance through autophagy reactivation offers a promising strategy to enhance the curative potential of combined modality therapies.

While this study primarily focuses on ER-positive breast cancer, the mechanistic insights into ESR1’s role in autophagy may have broader implications across hormone-driven malignancies. Future research is encouraged to explore whether similar autophagy regulatory networks exist in other estrogen-responsive cancers such as endometrial or ovarian tumors, potentially extending the impact of these findings beyond breast cancer.

In-depth molecular analysis revealed that ESR1 signaling dampens p62/SQSTM1 transcription and impairs its functional interactions with ubiquitinated cargo, which are critical for selective autophagy initiation. Reversing this repression through ESR1 targeting releases autophagic inhibition, facilitating enhanced clearance of cellular debris and promoting apoptotic cascades under stress conditions. Such mechanistic clarity strengthens the foundation for rational drug design aimed at modulating this axis.

Moreover, the study underscores the dynamic nature of cancer cell adaptation, whereby hormonal signaling pathways intersect with intracellular degradation systems to fine-tune survival responses. This crosstalk provides a fertile ground for discovering vulnerabilities unique to cancer cells, distinct from normal tissue counterparts, thereby minimizing off-target effects and improving therapeutic index.

The authors advocate a multidisciplinary approach to further refine ESR1-autophagy interactions, including protein structural studies and in vivo imaging of autophagic flux in clinical samples. These efforts will be crucial to translate preclinical observations into robust clinical interventions that can improve patient survival and quality of life in ER-positive breast cancer.

Ultimately, by charting a previously uncharted territory between estrogen receptor function and autophagy regulation, this seminal study sets a new standard for innovative cancer research. It challenges the research community to rethink existing biological paradigms and leverage molecular synergies for designing next-generation cancer therapeutics tailored to the complex biology of hormone-responsive tumors.

In conclusion, the restoration of SQSTM1-dependent autophagy through precise targeting of ESR1 constitutes a highly promising therapeutic strategy to sensitize ER-positive breast cancer cells to oxidative and radiation stress. This insight not only deepens our understanding of breast cancer biology but also offers an exciting clinical translational opportunity that could significantly improve outcomes for patients battling this prevalent and often formidable disease.

Subject of Research: Restoration of SQSTM1-dependent autophagy via ESR1 targeting in ER-positive breast cancer and its impact on sensitization to oxidative and radiation stress.

Article Title: Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress.

Article References:
Yang, YF., He, ZJ., Kuo, HH. et al. Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress. Cell Death Discov. 11, 451 (2025). https://doi.org/10.1038/s41420-025-02755-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02755-8

Hormone receptor-positive and HER2-negative breast cancer remains the most frequently diagnosed subtype worldwide. Despite advances in early detection and localized treatments, Stage IV metastatic disease presents significant challenges both clinically and emotionally. Treatment regimens have expanded considerably, encompassing next-generation endocrine therapies such as selective estrogen receptor degraders (SERDs), third-generation aromatase inhibitors (AIs), and a variety of targeted agents inhibiting key pathways like CDK4/6, PI3K, and mTOR. Furthermore, antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) have introduced novel mechanisms of action that improve survival outcomes. However, with an increasing arsenal of therapies, doctors and patients alike face complex decisions balancing efficacy with safety and quality of life.

The innovative study spearheaded by Arpino, De Angelis, Gerratana, and colleagues addressed this complexity by engaging 102 Italian patients diagnosed with Stage IV HR+ HER2− metastatic breast cancer. Participants were presented with a series of hypothetical treatment choices characterized by differing attributes such as progression-free survival (PFS) benefits and the likelihood of severe side effects, particularly grade 3 or higher adverse events (AEs). Employing a discrete choice experiment methodology enabled the researchers to quantify the relative importance patients assign to these attributes, capturing trade-offs that are otherwise difficult to measure.

Key findings from the study reveal a clear prioritization of treatment efficacy among patients. Progression-free survival emerged as the most valued attribute, indicating that patients strongly desire therapies that can extend the period during which their disease does not worsen. This preference underscores the hope patients place on durable disease control, which not only translates into longer life expectancy but also the opportunity to maintain better health and daily functioning for longer intervals. Importantly, this preference remained consistent across diverse patient subgroups, emphasizing its universal relevance in metastatic breast cancer care.

Equally noteworthy was the ranking of safety considerations. The risk of experiencing grade 3 or higher adverse events was identified as the second most crucial treatment characteristic. Severe side effects, which can range from significant fatigue and infections to more debilitating toxicities, substantially impact patients’ quality of life and willingness to adhere to prescribed regimens. This finding highlights the intricate balance patients seek: maximizing therapeutic benefit while minimizing harmful sequelae. It offers a vital insight for clinicians and drug developers as they strive to tailor treatments that align with patient priorities.

The Italian study further underscored how differential side effect profiles underpin treatment preferences. For instance, therapies with a favorable tolerability profile, reducing the incidence of severe AEs, significantly swayed patient choices even when efficacy gains were comparable. Such nuances indicate that patient-centered care must move beyond efficacy metrics alone and incorporate comprehensive evaluation of adverse event burdens. This approach may foster better acceptance and satisfaction with chosen therapies, potentially enhancing overall healthcare outcomes.

Notably, the application of discrete choice experiments deepens our understanding of patient decision-making in oncology, a field traditionally dominated by physician-led treatment algorithms. This quantitative approach simulates real-life trade-offs by forcing respondents to elect between competing interventions with variable attributes, presenting a more realistic appraisal of how patients may behave when confronted with actual therapeutic options. The strength of this methodology lies in its ability to capture nuanced preferences that can guide shared decision-making processes and inform regulatory and reimbursement policies.

This research also signals a shift toward personalized medicine encompassing patient preference integration, an aspect often overlooked in clinical trials that primarily focus on survival endpoints and toxicity incidence. By incorporating patient valuations of treatment attributes, healthcare providers may better align therapy choices with individual patient values, promoting adherence and satisfaction. The findings highlight that patients are not passive recipients but active partners in their care, bringing unique perspectives that can transform healthcare delivery.

Furthermore, the researchers emphasized that understanding preference heterogeneity is essential as patient situations evolve. Factors such as previous treatments, comorbidities, age, and social support networks can modulate how patients evaluate treatment options. While efficacy generally dominates preferences, some patient segments may weigh adverse events or mode of administration more heavily, suggesting the need for flexible, context-sensitive decision frameworks. These insights advocate for routine incorporation of structured preference assessments in clinical consultations.

Beyond clinical care, these findings resonate with drug development pipelines and health technology assessments. Pharmaceutical companies can leverage patient preference data to prioritize development of compounds with balanced efficacy and safety profiles that resonate with patient needs. Regulators and payers might also consider such data in evaluating the value and reimbursement of novel agents, potentially accelerating access to treatments that patients genuinely favor.

This seminal work from Italy highlights an emerging trend where patient-centered outcomes research intersects with pharmacology, oncology, and health economics. By quantifying what matters most to patients living with challenging metastatic breast cancer, the study empowers physicians and stakeholders to make informed, empathetic choices that transcend traditional clinical metrics. It represents an important step toward harmonizing medical innovation with lived patient experience.

As metastatic HR+ HER2− breast cancer continues to challenge researchers and clinicians globally, integrating patient preferences into therapeutic decision-making may improve survival outcomes and quality of life alike. Future research expanding on these findings could explore longitudinal changes in preferences as treatments advance and disease trajectories evolve. Additionally, cross-cultural studies might reveal geographic variations that inform localized strategies for patient engagement.

In conclusion, this discrete choice experiment conducted among Italian patients unveils that treatment efficacy, particularly progression-free survival, remains the foremost priority for Stage IV HR+ HER2− metastatic breast cancer patients. Close behind is the imperative of minimizing severe adverse events, reinforcing the delicate balance patients seek in treatment decisions. Through methodical and patient-focused inquiry, this study illuminates the path toward more personalized, value-driven oncology care where patient voices steer therapeutic journeys.

Such insights affirm that the future of metastatic breast cancer treatment lies not only in scientific advances but equally in embracing the patient experience. Aligning clinical excellence with patient preferences promises to elevate care standards and transform outcomes in this complex disease setting.

Subject of Research: Patient treatment preferences in hormone receptor-positive/HER2-negative metastatic breast cancer

Article Title: Patient preferences for treatments in hormone receptor-positive/HER2-negative metastatic breast cancer in Italy: a discrete choice experiment study

Article References:
Arpino, G., De Angelis, C., Gerratana, L. et al. Patient preferences for treatments in hormone receptor-positive/HER2-negative metastatic breast cancer in Italy: a discrete choice experiment study. BMC Cancer 25, 920 (2025). https://doi.org/10.1186/s12885-025-14308-4

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14308-4