The central concept guiding this research is the tumor microenvironment, or TME, the scaffold of extracellular matrix within which tumor cells and host immune cells communicate and compete. Many cancers are described as immunologically cold, meaning they contain few functional cytotoxic immune cells and resist the effects of immune checkpoint inhibitors, the landmark therapies that block inhibitory receptors such as PD-1 and PD-L1 to unleash CD8-positive T cells. Checkpoint inhibitors have transformed survival for many patients since emerging in the 1990s, but their efficacy is throttled by features of the TME, including low T cell numbers, T cell exhaustion, oxygen-starved tissue, and dense populations of immunosuppressive cells. The review’s authors, led by Campbell M. Johnston and Hongji Zhang of the University of Virginia’s Department of Surgery, argue that exercise directly counters many of these barriers, effectively warming cold tumors and sensitizing them to drugs that were previously powerless against them.

One of the most detailed lines of evidence concerns tumor-associated macrophages, or TAMs, immune cells that are abundant within cold tumors and frequently promote malignancy. TAMs exist along a spectrum from the M1 phenotype, which fights tumors, to the M2 phenotype, which secretes immunosuppressive molecules such as interleukin-4, interleukin-10, PD-L1, and transforming growth factor-beta that blunt effector T cell function and empower regulatory T cells. Worse, TAMs can push CD8-positive T cells into a terminally exhausted state from which they cannot recover, and hypoxia accelerates this process. In mouse models of glioblastoma, depleting TAMs increased the proportion of stem-like progenitor-exhausted T cells and improved responsiveness to anti-PD-1 therapy, underscoring how central these cells are to treatment failure. Preclinical studies now show that aerobic exercise can tip the balance, repolarizing macrophages from the pro-tumor M2 state toward the anti-tumor M1 state and reducing total M2 numbers within tumors.

The macrophage data are remarkably consistent across exercise modalities. Breast cancer-bearing mice that ran on treadmills before and after tumor inoculation showed fewer M2 macrophages within their tumors, while medium-intensity treadmill running increased the M1-to-M2 ratio in similar models. In melanoma-inoculated mice, swimming prevented M2 polarization and reduced interleukin-6 production, inhibiting tumor glycolysis and lowering lactic acid accumulation. Exercise also increased the production of major histocompatibility complex class II molecules on macrophages, sharpening their ability to activate T cells. These findings matter clinically because pharmacological strategies targeting macrophage biology, including inhibitors of transforming growth factor-beta, have struggled in human trials, failing to show clear benefit or producing severe adverse events. Exercise, by contrast, achieves a similar biological reprogramming without toxicity, offering a route around a therapeutic bottleneck that has frustrated drug developers.

Myeloid-derived suppressor cells, or MDSCs, represent a second immunosuppressive population that exercise appears to tame. These cells promote immune evasion by impairing chemokine secretion, recruiting regulatory T cells, and increasing PD-1 expression on T cells. Multiple preclinical studies show that physical activity delays MDSC accumulation and reduces their numbers within tumors. Mice exercised before and after breast carcinoma inoculation had significantly lower intratumoral MDSC levels than sedentary controls, and treadmill running started after tumor inoculation reduced splenic MDSCs, slowed tumor progression, and increased immune cell infiltration in mammary carcinoma models, with an inverse relationship between MDSC abundance and CD8-positive T cell presence. Crucially, these findings extend to humans. In newly diagnosed breast cancer patients, a single session of acute exercise increased natural killer and CD8-positive T cell levels while reducing MDSCs. In esophageal cancer patients who exercised during neoadjuvant chemotherapy, CD8-positive T cell counts rose while inflammatory biomarkers associated with MDSCs and TAMs fell significantly.

Hypoxia and disordered blood vessel growth form a third pillar of the exercise-immunotherapy connection. Tumors grow so erratically that their vasculature becomes tangled and inefficient, starving tissue of oxygen and stabilizing hypoxia-inducible factors that drive further abnormal angiogenesis. The resulting hypoxic environment excludes natural killer and CD8-positive T cells, inhibits dendritic cells and antigen presentation, recruits immunosuppressive cells, and pushes macrophages toward the pro-tumor M2 phenotype through a CXCL8-interleukin-10 signaling axis, all of which correlate with poor prognosis and resistance to checkpoint blockade. Exercise directly counters this vicious cycle. Melanoma-bearing mice that swam at low or moderate intensity showed significantly reduced expression of hypoxia and glycolysis genes, along with greater CD8-positive T cell infiltration and cytotoxicity. Daily high-intensity exercise lowered intratumoral hypoxic fractions in breast carcinoma models, and in a landmark clinical observation, pancreatic cancer patients who exercised during preoperative therapy showed increased tumor vascularity, while exercised mice bearing patient-derived pancreatic tumors displayed vascular remodeling, accelerated regression, and delayed regrowth.

Natural killer cells, the innate immune system’s front-line tumor killers, emerge as perhaps the cells most responsive to exercise. NK cells mobilize more readily into tumors in exercised animals, and work by Cho and colleagues showed that NK cells from exercised individuals kill target cells more efficiently, with their cytotoxicity actually enhanced under hypoxic conditions, a striking advantage given the oxygen-poor nature of tumors. This resilience stems from exercise-induced metabolic reprogramming that reduces mitochondrial oxidative stress and, through interleukin-15 signaling, lessens sensitivity to reactive oxygen species such as hydrogen peroxide within the tumor microenvironment. Clinical translation is already visible: men with localized prostate cancer who adhered strictly to high-intensity interval training showed significantly increased NK cell infiltration into their tumors. Perhaps most dramatic, Pedersen and colleagues found that voluntary wheel running reduced tumor volume by 66 percent in mice lacking functional T cells, an effect abolished when NK cell production was blocked, proving that NK cells alone can mediate exercise-driven tumor suppression.

CD8-positive T cells, the primary targets of checkpoint inhibitors, are recruited into exercised tumors through well-defined molecular routes. The chemokine receptor CXCR3, which binds CXCL9, CXCL10, and CXCL11, guides these cells into tumor tissue, and CXCR3 knockout mice show reduced T cell infiltration and blunted responses to PD-1 blockade. Recent work demonstrated that four weeks of preoperative treadmill running increased CXCL9 release and CXCR3-positive T cell recruitment in colorectal liver metastases, an effect lost in CXCL9-deficient mice. Exercise also suppresses CCL5, a chemokine that recruits regulatory T cells, TAMs, and MDSCs and correlates with poor prognosis, while boosting interleukin-15, a cytokine essential for T cell survival that appears to actively shift CD8-positive cells from circulation into tumors rather than merely raising their blood counts.

The combination studies provide the most compelling case. Melanoma-bearing mice treated with exercise plus anti-PD-1 therapy developed smaller tumors with more apoptotic cells, more cytotoxic T cells, and fewer regulatory T cells than mice receiving the drug alone. Similar synergy appeared in triple-negative breast cancer, where treadmill running improved therapeutic response, boosted T cell and NK cell activation, and cut MDSC numbers alongside anti-PD-1 treatment. In transgenic breast cancer models, adding running to anti-PD-1 therapy delayed tumor growth and improved control, even when both interventions began only after tumors reached a clinically relevant size. Pancreatic ductal adenocarcinoma, notoriously resistant to checkpoint inhibitors, responded to low-intensity treadmill running combined with anti-PD-1 when neither approach worked alone, an especially promising result for patients too ill for vigorous activity. Clinically, hepatocellular carcinoma patients who exercised regularly had significantly better overall and progression-free survival on combined lenvatinib and anti-PD-1 therapy, with matching results in mouse models. Randomized trials such as HI AIM and ERICA are now testing supervised exercise before and during immunotherapy infusions in lung cancer patients.

The authors are careful to note that clinical evidence remains limited and that major questions persist regarding optimal exercise modality, intensity, frequency, timing, and patient selection across cancer types, ages, sexes, disease stages, and body mass indices. Yet the biological coherence of the evidence is difficult to dismiss: exercise relieves hypoxia, normalizes vasculature, repolarizes macrophages, suppresses MDSCs and regulatory T cells, mobilizes NK cells, and drives cytotoxic T cells into tumors through defined chemokine axes, collectively converting cold tumors into inflamed, drug-responsive ones. If ongoing adequately powered trials with longitudinal immune profiling confirm these mechanisms in patients, structured physical activity could become one of the first universally accessible adjuncts to cancer immunotherapy, a prescription written not on a pharmacy pad but into the daily routines of patients fighting some of medicine’s most treatment-resistant cancers.

Subject of Research: How physical exercise modulates the tumor microenvironment to enhance cancer immunotherapy efficacy

Article Title: Physical Exercise in Immunotherapy

Article References: Johnston, C. M., Kim, S. J., Zhang, Y., Tsung, C., Kent, E., May, A., & Zhang, H. (2026). Physical Exercise in Immunotherapy. Sports Medicine – Open, 12(1), Article 130. https://doi.org/10.1186/s40798-026-01101-1

Image Credits: AI Generated

DOI: 10.1186/s40798-026-01101-1

Keywords: physical exercise, cancer immunotherapy, immune checkpoint inhibitors, tumor microenvironment, tumor-associated macrophages, myeloid-derived suppressor cells, natural killer cells, CD8 T cells, PD-1, tumor hypoxia, interleukin-15, cold tumors

ZBP1 is best known for antiviral sensing, but recent work has expanded its role to recognize Z-DNA and Z-RNA structures produced during cellular stress. These Z-form nucleic acids can arise when endogenous retroelements become activated, when splicing goes awry, when R-loops accumulate, or when “viral mimicry” signals are generated by nonviral events.

The Review emphasizes why treatment response varies so widely among patients. Many therapies aim to increase genomic stress to kill tumor cells, yet immune activation often remains weak. ZBP1 is presented as a molecular checkpoint that detects stress-associated nucleic acids and initiates necroptosis, a regulated, highly inflammatory form of cell death.

Unlike apoptosis, necroptosis can amplify immune priming. By promoting the release of tumor antigens and damage-associated molecular patterns (DAMPs), ZBP1-mediated necroptosis may enhance dendritic cell activation and improve downstream T-cell responses.

A central mechanistic theme is the coupling between ZBP1 signaling and oxidative stress. Once activated, ZBP1 engages the RIPK1–RIPK3–MLKL signaling axis to drive necroptosis, while reactive oxygen species (ROS) both promote ZBP1 pathway activation and intensify necroptotic execution.

This creates a feed-forward circuit in which oxidative stress acts as both regulator and amplifier. The Review positions redox biology not as a background factor, but as an active driver of inflammatory signaling that can strengthen antitumor immunity.

The authors also explore therapeutic strategies designed to induce Z-form nucleic acids. They discuss combinations involving epigenetic modulators, curaxins, and splicing inhibitors—approaches that can raise intracellular levels of Z-nucleic acids and thereby activate ZBP1.

To increase selectivity, the Review proposes pairing ZBP1 activation with localized ROS-generating methods or nanomedicine platforms. In principle, this could preferentially trigger immunogenic necroptosis within tumors, increasing immune cell recruitment and improving responsiveness to immune checkpoint blockade.

Finally, the Review outlines translational hurdles: identifying biomarkers that reflect ZBP1 pathway activity, optimizing drug combinations, understanding tumor-specific control of necroptosis, and reducing risks of unwanted inflammatory toxicity. Overall, it reframes ZBP1 as a key bridge between genomic stress sensing, regulated cell death, and durable antitumor immune activation.

Subject of Research: Cells
Article Title: ZBP1-mediated sensing of genomic stress in cancer therapy
News Publication Date: 8-Jul-2026
Web References: https://www.sciexplor.com/fos ; http://dx.doi.org/10.70401/fos.2026.0035
References: Literature review
Image Credits: Not provided

Keywords: ZBP1, genomic stress, Z-DNA, Z-RNA, necroptosis, RIPK1–RIPK3–MLKL, ROS, oxidative stress, cancer immunotherapy, viral mimicry

The therapeutic paradigm shift explored in this trial capitalizes on the transformative potential of radiotherapy to convert PDAC tumors from immunologically “cold”—meaning unresponsive to immune attacks—to “hot,” thereby sensitizing them to immunotherapy. The immunogenic conversion fundamentally enhances the tumor’s susceptibility to immune checkpoint inhibitors, specifically anti-programmed cell death protein 1 (PD-1) targeted therapy. This strategic synergy aims to amplify the immune system’s ability to recognize and eradicate tumor cells, which traditionally evade detection in this cancer subtype.

Ivonescimab represents a new frontier in immunotherapy as a bispecific antibody adept at simultaneously targeting PD-1 and vascular endothelial growth factor (VEGF). By inhibiting VEGF, Ivonescimab not only disrupts tumor angiogenesis—a vital process for tumor growth and metastasis—but also modifications the pancreatic cancer microenvironment. VEGF blockade remodels this typically immunosuppressive environment into one that permits immune effector cells to infiltrate and attack the malignancy more effectively when combined with PD-1 inhibition.

The clinical trial, registered under NCT06844422, is designed as a single-arm, Phase Ib/II study, involving 37 patients diagnosed with LAPC. The Phase Ib segment primarily focuses on establishing the maximum tolerated dose (MTD) and identifying any dose-limiting toxicities (DLTs) of Ivonescimab. Employing a classical 3+3 dose-escalation design over four weeks, researchers meticulously titrate the dosage to define a recommended Phase II dose (RP2D), ensuring maximum efficacy blended with manageable safety profiles.

Transitioning into Phase II, the trial’s endpoint sharpens its focus on progression-free survival (PFS), a critical metric indicative of therapeutic benefit in this context. Patients receive the RP2D of Ivonescimab in conjunction with precise SBRT administration—a regimen delivering radiation doses ranging between 25 to 50 Gy over five fractions within two weeks—followed by tailored cycles of modified FOLFIRINOX chemotherapy. This chemotherapy combination, consisting of oxaliplatin, irinotecan, leucovorin, and fluorouracil, remains a cornerstone therapy for pancreatic cancer and is leveraged here to maximize cytotoxic effects synergistically with Ivonescimab and radiation.

A notable aspect of the study design is its emphasis on maintenance therapy. Patients who tolerate the combination regimen can continue with Ivonescimab monotherapy for up to 12 months or until disease progression or intolerable toxicity arises. This approach aims to sustain immune pressure on the tumor, potentially prolonging remission and delaying resistance.

The rationale underlying this multifaceted treatment strategy resides in recent translational research revealing that PDAC’s notoriously hostile tumor microenvironment attenuates the efficacy of single-modality immunotherapies. By strategically combining SBRT, chemotherapy, and dual blockade of PD-1 and VEGF pathways, the trial hopes to surmount the barriers posed by the dense stromal environment and immunosuppressive signals prevalent in PDAC.

Previous preclinical and clinical studies have hinted at the potential of anti-VEGF therapies to normalize tumor vasculature, decrease hypoxia, and reduce regulatory T-cell populations, collectively fostering a milieu more amenable to immune attack. Similarly, the use of stereotactic body radiotherapy offers localized high-dose radiation capable of releasing tumor antigens and upregulating immunogenic markers, further enhancing systemic anti-tumor immune responses.

Safety remains a paramount concern in this vulnerable patient population, and the Phase Ib segment’s structured dose-escalation ensures rigorous monitoring of adverse events. Dose-limiting toxicities, if observed, will inform dose adjustments to balance maximal therapeutic efficacy with patient safety—a critical consideration given the combinatorial therapy’s intensity.

The implications of this trial extend beyond individual patient outcomes. Should the therapy demonstrate a significant extension in progression-free survival or overall survival, it could reshape first-line treatment protocols for LAPC, a disease for which curative options remain circumscribed. Moreover, the study’s findings can catalyze further research into bispecific antibody therapies that simultaneously target multiple axes of tumor progression and immune evasion.

This trial also underscores the mounting significance of precision oncology, wherein treatments are no longer one-size-fits-all but intricately tailored based on the tumor’s immunobiological characteristics and microenvironmental context. The integration of advanced imaging, cytological analyses, and molecular profiling before enrollment exemplifies the meticulous patient selection aimed at optimizing therapeutic responsiveness.

The investigators anticipate that success in combining Ivonescimab with guided SBRT and chemotherapy could establish a new standard of care, mitigating the high morbidity associated with pancreatic cancer. Furthermore, the exploration of immune checkpoint and VEGF co-inhibition may open therapeutic avenues for other solid tumors marked by similar immunosuppressive microenvironments.

As the trial progresses, its rigorous methodology and innovative approach will contribute invaluable insights into the treatment resistance mechanisms intrinsic to pancreatic cancer. This knowledge will not only assist oncologists in clinical decision-making but may also drive the development of next-generation immunotherapeutic agents.

Early data dissemination from this study could also invigorate the oncology community’s efforts toward combinatorial immunotherapy regimens, highlighting how traditional treatments, like radiotherapy and chemotherapy, can synergistically complement immunomodulatory drugs. Such multidisciplinary approaches reflect the evolving complexity and sophistication in cancer management strategies.

In conclusion, this trial represents a bold and innovative stride against a formidable adversary in pancreatic cancer. By harnessing Ivonescimab’s dual-targeting capabilities alongside precise radiotherapy and chemotherapy, researchers aspire to tip the balance in favor of durable remission and improved quality of life for patients facing this daunting diagnosis. The oncology field awaits the results eagerly, which promise to be a pivotal chapter in the ongoing battle against PDAC.

Subject of Research: The study investigates the efficacy and safety of Ivonescimab, a bispecific antibody targeting PD-1 and VEGF, combined with stereotactic body radiotherapy (SBRT) and chemotherapy in patients with locally advanced pancreatic cancer (LAPC).

Article Title: Study protocol for a single-arm phase Ib/II trial of Ivonescimab combined with adapted guided stereotactic body radiotherapy and chemotherapy in patients with locally advanced pancreatic cancer.

Article References:
Tang, Z., Shi, F., Zhu, K. et al. Study protocol for a single-arm phase Ib/II trial of Ivonescimab combined with adapted guided stereotactic body radiotherapy and chemotherapy in patients with locally advanced pancreatic cancer. BMC Cancer 25, 1581 (2025). https://doi.org/10.1186/s12885-025-14944-w

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14944-w

Immunotherapy has revolutionized oncology by harnessing the immune system’s intrinsic ability to identify and eliminate malignant cells. Central to this approach are immune checkpoint inhibitors, which unleash T cells—the immune system’s foot soldiers—by blocking proteins that typically restrain immune activation to protect healthy tissues. Despite considerable advances, a significant proportion of cancer patients fail to respond to these treatments, often due to an immunologically “cold” tumor microenvironment that lacks sufficient T cell infiltration and activation.

This study focuses on the cyclin-dependent kinases CDK12 and CDK13, genes implicated in DNA repair and transcriptional regulation. Prior investigations had linked loss of CDK12 to aggressive disease phenotypes in prostate cancer, particularly metastatic forms. Building on these insights, the team conducted sophisticated preclinical experiments that revealed how the simultaneous inactivation of CDK12 and CDK13 induces DNA damage through dysregulated transcriptional processes and DNA replication stress, effectively unleashing intracellular DNA fragments.

These cytosolic DNA fragments act as danger signals, triggering activation of the stimulator of interferon genes (STING) pathway. STING functions as a molecular sentinel within tumor cells, detecting aberrant DNA and initiating a powerful innate immune response characterized by type I interferon production and recruitment of immune effector cells. Upon activation via CDK12/13 loss, the STING pathway orchestrates the infiltration and activation of tumor-infiltrating lymphocytes, particularly CD8+ T cells, which are essential for antitumor immunity.

What renders this mechanism especially compelling is its ability to sensitize previously unresponsive tumors to immune checkpoint blockade. The research team demonstrated, through the administration of a novel CDK12/13 degrader, that mice bearing tumors with suppressed CDK12/13 expression exhibited enhanced STING signaling and increased T cell-mediated tumor control when treated with checkpoint inhibitors. This convergence of innate and adaptive immune activation holds the potential to overcome resistance mechanisms that plague current therapies.

Furthermore, comprehensive analysis of clinical tumor samples across a variety of cancer types substantiated the preclinical findings. Inactivation of both CDK12 and CDK13 correlated strongly with elevated STING activity and more favorable outcomes following immunotherapy. This cross-cancer relevance underscores the universal applicability of this therapeutic strategy beyond prostate cancer, potentially benefiting patients across a wide oncology spectrum.

At the molecular level, the study elucidates how CDK12/13 regulate the transcriptional elongation of genes necessary for DNA repair and replication. When these kinases are inhibited or genetically inactivated, unscheduled accumulation of replicative stress and aberrant RNA processing occur. The resulting DNA breaks and fragments escaping into the cytosol provide the critical substrates for cyclic GMP-AMP synthase (cGAS) activation and subsequent STING signaling, thereby converting the tumor into a nidus for immune recognition.

The implications of these discoveries extend beyond mechanistic insight. The CDK12/13 degrader molecule employed serves as a prototype for a new class of targeted agents designed to amplify innate immune sensing within the tumor microenvironment. Its combination with approved immune checkpoint therapies could form the basis of clinical trials aimed at enhancing response rates and expanding the therapeutic window for patients with refractory cancers.

Despite promising results, the authors caution that clinical translation requires rigorous validation. Dr. Arul Chinnaiyan, leading the research, highlights the urgency of exploring CDK12/13 degraders combined with immune checkpoint inhibitors in human trials to determine safety, efficacy, and optimal dosing strategies. Should these translational efforts succeed, this approach could recalibrate the landscape of immuno-oncology and solidify a new paradigm for breast, lung, prostate, and other malignancies.

This innovative research also casts a spotlight on the interplay between transcriptional regulation, DNA damage repair pathways, and immunity—a multifaceted axis increasingly recognized as central to cancer biology. By manipulating this axis, researchers can transform immune deserts into immune hotspots, empowering the immune system to execute more effective tumor eradication.

In addition to academic implications, this discovery carries substantial translational potential. Given that several pharmaceutical companies and academic institutions are already invested in developing CDK inhibitors, these findings may accelerate the rational design of combination therapies involving immune modulation. Partnerships between academia, biotech, and pharma will be critical to rapidly deploy this strategy to improve patient outcomes in real-world clinical settings.

In sum, the University of Michigan-led study reveals a potent and actionable vulnerability in cancer cells: disabling CDK12 and CDK13 unleashes a cascade of innate immune responses via STING, which in turn primes tumors for successful immune checkpoint therapy. This dual-targeting maneuver represents a leap forward in leveraging the cancer-immune interface and could herald a new era of more effective, durable anti-cancer treatments.

Subject of Research: Animals

Article Title: CDK12/13 inactivation triggers STING-mediated anti-tumor immunity in pre-clinical models

News Publication Date: 23-Jul-2025

Web References:
https://doi.org/10.1172/JCI193745

References:
“CDK12/13 inactivation triggers STING-mediated anti-tumor immunity in pre-clinical models,” The Journal of Clinical Investigation

Image Credits: Arul Chinnaiyan

Keywords: Health and medicine