The research team, led by Damir Zubac together with Timo Sonntag, Diana Kranjc and Freerk T. Baumann, recruited 19 patients undergoing acute immune checkpoint inhibitor treatment and 21 age-matched healthy controls from the Cologne area. Participants were screened to exclude hypertension, diabetes, chronic lung disease and obesity, and were required to be free of brain, bone or lung metastases. The patients, who had been diagnosed roughly 14 months earlier and had been on immunotherapy for about six months, most commonly had malignant melanoma or breast cancer, with the majority treated with the PD-1 antibodies pembrolizumab or nivolumab. Crucially, the two groups were well matched: there were no significant differences in age, height, body mass, body mass index, resting blood pressure, oxygen saturation or body composition measured by bioelectrical impedance.

Each participant completed two laboratory visits. In the first, they performed a ramp-based cardiopulmonary exercise test on a cycle ergometer to exhaustion, with breath-by-breath measurement of pulmonary gas exchange to determine peak oxygen uptake, peak power output, the gas exchange threshold and the oxygen uptake efficiency slope. In the second session, they completed the Multidimensional Fatigue Inventory questionnaire, a validated 20-item instrument covering general, physical, mental fatigue, reduced activity and reduced motivation, followed by a 30-minute steady-state cycling test at 90 percent of each individual’s gas exchange threshold, during which energy expenditure and gross cycling efficiency were calculated.

The results painted a clear picture of diminished physical capacity in the immunotherapy group. Patients showed significantly lower pulmonary ventilation, oxygen uptake, carbon dioxide production, stroke index and oxygen uptake efficiency slope during maximal testing, all with large effect sizes. Their exercise tests ended roughly four minutes sooner than those of controls, and the peak power output they achieved was dramatically lower, with an effect size of 2.35. Importantly, patients reported the same subjective effort at exhaustion, rating around 19 on the standard scale, meaning they were not simply holding back. The pattern of reduced oxygen pulse alongside only modest differences in maximal heart rate suggests that the limitation lies primarily in the heart’s ability to augment stroke volume and cardiac output during maximal effort, a finding the authors note could hint at early cardiotoxicity, though no direct cardiac diagnostics were performed.

Fatigue, however, was the most dramatic group difference of all. Using age- and sex-standardized cutoffs derived from a representative German community sample, 63 percent of the immunotherapy patients met criteria for clinically relevant chronic fatigue, compared with just 15 percent of the healthy controls. Across all five dimensions of the questionnaire, patients scored substantially worse: general fatigue was elevated by 38 percent, physical fatigue by nearly 40 percent, and mental fatigue, reduced activity and reduced motivation were all similarly increased with moderate to large effect sizes.

Yet when the researchers ran linear regression models asking whether peak oxygen uptake or peak power output, adjusted for age, could predict general fatigue scores, the answer was a consistent no. In healthy controls, the models explained between 8 and 13.5 percent of the variance in fatigue, and in immunotherapy patients only between 4.3 and 5.6 percent, none of it statistically significant. Age, too, failed to predict fatigue, despite the common assumption that aging drives both declining fitness and increasing tiredness. Multicollinearity diagnostics were clean, so the null result was not a statistical artifact of correlated predictors.

A particularly novel observation emerged from the submaximal endurance test. Although every single participant, patient and control alike, managed to complete the full 30 minutes of moderate-intensity cycling at 90 percent of their gas exchange threshold, the patients did so at significantly lower gross efficiency. The average workload was 122 watts for controls versus 88 watts for patients, and the patient group converted metabolic energy into mechanical work measurably less efficiently, with a mean group difference of just over two percentage points. Because similar data in checkpoint inhibitor populations do not otherwise exist, the authors can only hypothesize that impaired mitochondrial coupling in skeletal muscle, a phenomenon previously demonstrated with in vivo phosphorus magnetic resonance spectroscopy in older adults, may underlie the inefficiency. Supporting this idea, recent muscle biopsy work has shown that even a single chemotherapy dose induces mitochondrial dysfunction in breast cancer patients.

The disconnect between how tired patients feel and how their bodies perform on objective testing carries real clinical weight. Structured exercise is recommended as a first-line therapy for cancer-related fatigue, and prior work in immunotherapy-treated patients has shown that exercise interventions can reduce fatigue scores by roughly 8 to 10 points on validated scales. The present findings suggest that a clinically meaningful level of fatigue does not preclude moderate-to-vigorous aerobic exercise: all 19 fatigued patients completed a half hour of cycling under controlled conditions. This supports the feasibility of individualized aerobic exercise prescriptions, calibrated to objective test results rather than to how patients subjectively rate their energy.

The authors are careful to frame the study as exploratory. The cross-sectional design, the modest sample size of 40 analyzed participants, the heterogeneity of cancer diagnoses and prior treatments, and the absence of direct cardiac or mitochondrial measurements all limit how far the conclusions can be pushed. The findings characterize people receiving checkpoint inhibitor therapy rather than proving causal effects of the drugs themselves, and the regression models leave open the question of what actually drives chronic fatigue, with circulating inflammatory cytokines, muscle metabolic changes and neurotransmitter disruption all implicated in the wider literature.

Even so, the study marks a step beyond earlier feasibility and adherence work in this population. It provides the first data on work efficiency in patients under acute checkpoint inhibitor therapy, offers a physiological rationale for prescribing aerobic exercise at the gas exchange threshold, and points future investigators toward more comprehensive, non-invasive assessments of the oxygen transport pathway, such as flow-mediated dilation and vascular occlusion testing, to finally unravel why immunotherapy patients feel so tired even when their exercise capacity tells only part of the story.

Subject of Research: The relationship between self-reported chronic fatigue and objectively measured cardiopulmonary exercise parameters in adult cancer patients receiving immune checkpoint inhibitor therapy

Article Title: Chronic, self‐reported fatigue in adult immunotherapy patients and healthy controls: No association with cardiopulmonary exercise testing parameters

Article References: Zubac, D., Sonntag, T., Kranjc, D., & Baumann, F. T. (2026). Chronic, self‐reported fatigue in adult immunotherapy patients and healthy controls: No association with cardiopulmonary exercise testing parameters. Physiological Reports, 14(17), Article e71090. https://doi.org/10.14814/phy2.71090

Image Credits: AI Generated

DOI: 10.14814/phy2.71090

Keywords: immunotherapy, immune checkpoint inhibitors, chronic fatigue, cancer-related fatigue, cardiopulmonary exercise testing, VO2 peak, cycling efficiency, exercise oncology, cardiorespiratory fitness, MFI-20, mitochondrial dysfunction, supportive care

Oncotherapy, encompassing chemotherapy, radiation therapy, immunotherapy, targeted therapy, and their combinations, has become the cornerstone of modern cancer care. However, these treatments, designed to eradicate malignant cells, frequently disrupt normal physiological processes owing to their systemic nature. The review meticulously discusses the multifaceted biological mechanisms underlying therapy-induced toxicities, emphasizing the importance of understanding the molecular and cellular cascades that lead to both acute and chronic side effects. Hota and Mandal highlight that these unintended consequences are far from trivial—they often jeopardize patient quality of life and may even limit treatment efficacy by necessitating dose reductions or discontinuation.

One of the critical insights from this review is the recognition of oncotherapy-induced damage at the genomic and epigenomic levels. Treatments such as chemotherapy and radiation inflict DNA damage not only on cancer cells but also on healthy progenitor cells, contributing to mutagenesis and carcinogenesis over time. This genomic instability poses a paradoxical threat, potentially precipitating secondary malignancies—a grim reminder of the long-term risks intrinsic to these therapies. The authors urge the oncology community to refine therapeutic windows and develop agents that selectively target tumor cells while sparing healthy tissue.

Another pivotal discussion centers on the immune system’s complex response to oncotherapy. While immunotherapies aim to harness and amplify immune responses against tumors, their unintended impact includes provoking systemic inflammations and autoimmune-like reactions. These immune-related adverse effects, ranging from mild rashes to life-threatening pneumonitis, represent a formidable challenge that requires vigilant monitoring and personalized management protocols. The review posits that deeper immunological profiling could enable tailored interventions that optimize therapeutic outcomes while minimizing collateral damage.

The cardiovascular toxicities associated with oncotherapy also receive detailed scrutiny. Certain chemotherapeutic agents and targeted therapies are notorious for their cardiotoxic potential, inducing conditions such as congestive heart failure, arrhythmias, and hypertension. The review underscores the need for integrating cardio-oncology into routine care, advocating for proactive cardiac function assessments and the employment of cardioprotective strategies during cancer treatment. This holistic approach might safeguard patients’ cardiovascular health without compromising oncologic control.

Furthermore, the neurological complications stemming from oncotherapy are highlighted as a domain warranting greater attention. Neurotoxicity manifests in various forms, including peripheral neuropathy, cognitive dysfunction—often referred to as “chemo brain”—and sensory deficits, which profoundly undermine survivors’ functional capacity and emotional wellbeing. The authors stress the necessity of advancing neuroprotective agents and rehabilitation programs to address these burdensome side effects, which frequently remain underrecognized in clinical practice.

The review also elaborates on the reproductive and endocrine disruptions engendered by cancer treatments. Therapies targeting rapidly dividing cells can impair gonadal function, resulting in infertility, hormonal imbalances, and early menopause. These consequences not only affect survivorship but also exert significant psychosocial stress. Therefore, the authors advocate for integrating fertility preservation consultations and endocrine evaluations into oncologic care pathways, ensuring that patient-centered approaches address these often-neglected domains.

A particularly groundbreaking component of the review is the examination of the microbiome’s role in modulating oncotherapy side effects. Emerging evidence suggests that intestinal flora critically influence drug metabolism, immune responses, and mucosal integrity. Dysbiosis induced by chemoradiation may exacerbate gastrointestinal toxicities, leading to enteritis, diarrhea, and malnutrition. Hota and Mandal call for intensified research into microbiome-targeted interventions, proposing probiotics, prebiotics, and fecal microbiota transplantation as potential strategies to ameliorate these adverse effects.

Importantly, the review recognizes the heterogeneity of patient responses to oncotherapy side effects. Genetic predispositions, comorbidities, and environmental factors collectively shape toxicity profiles. The principles of pharmacogenomics and personalized medicine are thus imperative to forecast adverse effects and personalize treatment regimens. The authors anticipate that advances in biomarker discovery and machine learning will revolutionize prediction models, ushering in an era of truly tailored oncotherapy with minimized harm.

The socio-economic consequences of oncotherapy side effects are also discussed, underscoring the heightened healthcare utilization, loss of productivity, and diminished quality of life experienced by cancer survivors. The review advocates for comprehensive survivorship programs that offer psychological support, symptom management, and rehabilitation services, enabling patients to reclaim functional independence and social reintegration post-treatment.

In addition to the mechanistic insights, Hota and Mandal critically appraise current clinical trials and regulatory frameworks overseeing oncotherapeutic development. They call for heightened emphasis on side effect profiling, advocating that therapeutic approvals should integrate stringent assessments of long-term toxicity. Such regulatory vigilance, coupled with patient-reported outcome measures, will enhance the real-world relevance and safety of emerging cancer therapies.

Technological innovations such as nanomedicine and drug delivery systems also emerge as promising avenues to circumvent side effects. Targeted delivery platforms can potentially maximize tumor-specific drug concentrations while minimizing systemic exposure, thereby mitigating off-target organ damage. The review emphasizes that continuous collaboration between oncologists, biotechnologists, and pharmacologists is essential to translate these technologies into clinical realities.

Moreover, the review addresses the psychological toll of oncotherapy side effects, recognizing that anxiety, depression, and cognitive impairments contribute substantially to the overall disease burden. Integration of mental health services into oncology clinics is portrayed as a vital element of holistic care, ensuring that emotional wellbeing is preserved alongside physical health during treatment and survivorship.

Patient education and communication are highlighted as critical components in managing side effects effectively. Empowering patients with knowledge about potential toxicities, symptom reporting protocols, and coping strategies fosters adherence and alleviates uncertainties. The authors advocate utilizing digital health tools and telemedicine to enhance real-time monitoring and support, particularly for patients in remote or underserved regions.

Ultimately, Hota and Mandal’s review serves as a clarion call for intensified research efforts dedicated to unveiling and addressing the “hidden harms” of oncotherapy. By advancing mechanistic understanding, improving clinical management, and innovating therapeutic approaches, the oncology community can aspire to not only prolong survival but also safeguard the integrity of patients’ lives. The paradigm shift envisioned by this comprehensive exploration may usher in a future where cancer treatments are as gentle as they are effective, truly embodying the promise of precision medicine.

These findings illuminate the profound complexity of balancing efficacy and safety in cancer treatment. As cancer incidence continues to rise globally, the imperative to minimize the collateral damage of oncotherapy grows ever more urgent. Hota and Mandal’s scholarly synthesis stands out as an essential resource, one that robustly challenges practitioners and researchers alike to expand their horizons beyond tumor control and confront the full spectrum of therapeutic consequences.

As research accelerates and novel therapies emerge, ongoing vigilance and adaptability will be crucial to ensure that the benefits of oncotherapy decisively outweigh its harms. This review ultimately champions a more informed, compassionate, and scientifically rigorous approach to cancer care, promising a significantly improved quality of life for patients and survivors alike.

Subject of Research: Side effects and toxicities associated with various oncotherapy modalities, mechanisms underlying these effects, and strategies for mitigation.

Article Title: Unveiling the hidden harms: a review on the deeper exploration of side effects of oncotherapy.

Article References:
Hota, A., Mandal, B.K. Unveiling the hidden harms: a review on the deeper exploration of side effects of oncotherapy. Med Oncol 43, 75 (2026). https://doi.org/10.1007/s12032-025-03095-4

Image Credits: AI Generated

DOI: https://doi.org/10.1007/s12032-025-03095-4