Oncolytic virus therapy in the elderly: immune frailty, challenges, and perspectives.

Introduction

As global aging progresses, the incidence of newly diagnosed cancers is steadily rising. By 2050, it is estimated that approximately 35 million new cancer cases will occur annually worldwide ( 1 ). Presently, the elderly population (≥65 years) accounts for about 64% of new cancer cases and 71.3% of cancer-related deaths ( 2 ), with these proportions projected to increase further. Elderly cancer patients experience a distinct immune imbalance shaped by tumor-induced immunosuppression, age-associated immunosenescence, and inflammaging ( 3 , 4 ). This unique immunological state contributes to the high toxicity of conventional therapies, with grade 3–5 adverse events occurring in 53–83% of cases and a treatment-related mortality rate of 2% ( 5 ), alongside overall poor tolerance to therapy ( 6 ). Moreover, immune checkpoint blockade with PD-1/PD-L1 inhibitors exhibits limited effectiveness in older patients ( 7 ) and a higher risk of immune-related adverse events affecting the skin, kidneys, and gastrointestinal tract ( 8 , 9 ).

Oncolytic viruses (OVs), as a novel class of cancer immunotherapies, selectively infect tumor cells and induce immunogenic cell death (ICD), promoting the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens. Additionally, they activate the cGAS–STING innate immune pathway and stimulate type I interferon production, thereby converting immunologically “cold” tumors into “hot” ones ( 10 ). Notably, in the context of melanoma/sarcoma subgroups, OVs have achieved objective response rates of 26.4–32.9%, complete responses in 15.0%, durable response rates (DRR ≥ 6 months) in 16.3%, and extended the median duration of response to 33.7 months ( 11 , 12 ). However, the overall incidence of adverse events (AEs) related to OV therapy is 26.6%, nearly 2.07 times higher than in control groups ( 13 ). Furthermore, elderly patients remain severely underrepresented in OV trials, especially with those aged ≥70 years comprising only 17.7% of early-phase clinical studies ( 14 ). This lack of age-specific data casts doubt on the generalizability of OV findings to older populations.

Due to their distinctive immunosuppressive profiles ( 15 – 17 ), elderly patients undergoing OV therapy may be vulnerable to multiple complications, including the dual burden of immune overload and exhaustion ( 18 , 19 ), cytokine storm-induced inflammation ( 18 , 20 ), and compromised immune tolerance ( 21 – 23 ). This complex and multifactorial immune state heightens both the risks and limitations of OV-based therapy in the elderly, posing significant safety and efficacy challenges ( 24 – 26 ). Despite this, there is still a dearth of systematic investigations into the mechanisms of OV therapy under the backdrop of immune frailty in aging populations ( 14 ). Most existing studies rely on young or adult models and cohorts, leaving gaps in our knowledge regarding elderly-specific immune microenvironmental changes, virus–host interaction patterns, and optimal treatment timing ( 27 ).

This review seeks to elucidate the immunological features unique to elderly individuals and their interactions with OV therapy, focusing on three key questions ( Figure 1 ):

1. What are the pathophysiological characteristics of the immune microenvironment in elderly cancer patients? How do tumor-induced immunosuppression and age-related immunosenescence synergize at the molecular level to create a state of immune frailty? How does immunological vulnerability across different age stages affect immune function?

2. What unique immunotoxicities are associated with OV therapy in elderly patients? What are the mechanisms and clinical manifestations of the vicious cycle of immune overload and exhaustion, cytokine release syndrome, and loss of immune tolerance?

3. Why is it essential to prioritize the unique immune status of elderly cancer patients? Can precision interventions targeting immune frailty improve therapeutic windows? Can integrated strategies—such as immune reconstruction technologies, pharmacological optimization, and stratified management systems—maximize the benefits while minimizing the risks of OV therapy in older adults?How should this be achieved?

Unique immune frailty in elderly cancer patients

The immune microenvironment of elderly cancer patients (≥65 years) is distinctively complex ( 17 ), characterized by tumor-induced immunosuppression, age-related immunosenescence, and their synergistic disruption of immune homeostasis. Together, these factors constitute a unique state of immune frailty in elderly cancer patients.

Tumor-induced immunosuppression is commonly observed in this population ( Table 1 ). Specifically, cancer cells suppress effector T cell activity and function through the secretion of immunosuppressive cytokines such as transforming growth factor-β (TGF-β), interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF) ( 28 , 29 ). In addition, they activate suppressive metabolic pathways, including the denosine axis (CD39/CD73 → adenosine) and the tryptophan–kynurenine–AhR pathway (IDO1/IDO2/TDO2 → Kyn → AhR), further impairing T cell function ( 16 ). Tumor cells may also directly engage inhibitory immune checkpoints, such as programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), thereby inducing T cell apoptosis ( 30 ). Concurrently, the tumor immune microenvironment recruits and activates suppressive cell populations such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), both of which significantly inhibit antitumor immunity ( 31 ). The situation is further compounded by pro-inflammatory cytokines secreted via the senescence-associated secretory phenotype (SASP), including IL-6, IL-8, and TGF-β, which synergize with tumor-derived signals to exacerbate MDSC and Treg-mediated immunosuppression ( 17 ). This immunosuppressive milieu is frequently observed in elderly cancer patients and is associated with a reduced 5-year survival rate of just 38–50% among breast cancer patients aged over 70 years ( 32 ).

Age-related immunosenescence leads to thymic involution and a marked reduction in naïve T cells and T cell receptor (TCR) diversity and quantity, thereby compromising antigen recognition and immune responsiveness ( 15 , 33 ). Metabolic reprogramming also occurs in aged T cells, affecting mitochondrial function, glycolytic pathways, and chromatin accessibility, which diminishes the quality of both effector and memory T cells ( 15 , 34 ). In addition to T cell defects, age-related B cells (ABCs), particularly the T-bet+CD11c+ phenotype, become more prevalent, weakening humoral immune responses and impairing antigen-specific and antitumor immunity ( 35 ). Hematopoietic stem cells (HSCs) in the elderly exhibit a “myeloid bias” ( 19 ), resulting in increased MDSC production and activity, suppression of T cell function, and enhanced Treg expansion ( 36 ). Aging also impairs dendritic cell (DC) maturation, chemotactic ability, and cytokine secretion, leading to both quantitative and functional decline. Although natural killer (NK) cell numbers may increase with age, their cytotoxicity and cytokine production capacity are significantly diminished, compromising the first line of defense against tumors ( 37 , 38 ). Moreover, elderly individuals often present with “inflammaging,” a pro-inflammatory state strongly associated with adverse outcomes such as frailty and mortality. This state is marked by chronically elevated levels of IL-6 and TNF-α ( 39 ), which further promote myeloid skewing and MDSC expansion, suppress adaptive immunity, and contribute to a tumor microenvironment characterized by both immunosuppression and chronic inflammation ( 40 ). These immunosenescence-related changes collectively result in profound immunosuppression ( Table 2 ).

When tumor-induced immunosuppression coexists with age-related immunosenescence, their interplay gives rise to a vicious cycle of mutual reinforcement ( Table 3 ). Chronically elevated IL-6 activates the JAK/STAT3 signaling pathway, upregulating PD-L1 expression on tumor cells. It also inhibits tumor antigen presentation via the NMD/SMG1 pathway, thereby facilitating immune escape and further weakening antitumor immunity ( 41 , 42 ). SASP exacerbates immunosuppression by increasing the number of MDSCs and Tregs ( 17 ), upregulating Treg expression and FoxP3 levels ( 43 ). Tumor-derived extracellular vesicles (tEVs) carrying PD-L1 can induce T cell DNA damage and lipid metabolism reprogramming, thereby accelerating T cell senescence ( 44 ). Simultaneously, aged microenvironments release extracellular vesicles (aged-EVs) that remodel the tumor milieu to favor cancer progression. When combined with tEV-PD-L1, these factors further intensify immunosuppression ( 45 ). Tumor-secreted suppressive factors such as VEGF aggravate the existing decline in antigen presentation and IFN production capacity ( 46 ), leading to severely compromised tumor antigen recognition and presentation by antigen-presenting cells (APCs) like DCs ( 47 ).

Moreover, the degree of frailty across different stages of aging significantly impacts the immune system of elderly cancer patients ( Table 4 ). Patients with mild frailty (65–74 years, G8 score 15–17) typically exhibit only mild thymic involution. Naïve T cells are relatively preserved, baseline inflammatory markers such as IL-6 remain low (<5 pg/mL), MDSCs show only slight increases, and Tregs expand modestly (baseline +10–20%). As a result, these patients retain a 25–30% response rate to immunotherapy ( 48 , 49 ). In contrast, moderately frail patients (70–84 years or ≥3 comorbidities, G8 score 11–14) exhibit more pronounced thymic atrophy, significant reductions in TCR diversity, elevated inflammatory load (IL-6 at 5–15 pg/mL), 1.5–2-fold expansion of MDSCs, and a 30–50% increase in Tregs, resulting in reduced immunotherapy response rates of 15–25% ( 43 , 50 ). Severely frail patients (≥85 years or G8 score ≤10) show marked thymic atrophy, accumulation of terminally differentiated T cells (notably increased CD28–CD57+), and severe baseline inflammation (IL-6 >15 pg/mL). MDSCs are elevated by more than 2-fold, and Tregs expand by 50–80%, leading to immunotherapy response rates dropping below 15% ( 34 , 51 ). These frailty-related immune differences across age groups directly affect the efficacy of OV therapy by modulating immune responsiveness, ultimately influencing therapeutic outcomes and associated risks.

Novel immunological challenges of oncolytic virus therapy in elderly cancer patients

Oncolytic virus (OV) therapy presents several immunological challenges in elderly cancer patients, including immune overload, exhaustion of immune reserves, cytokine storm-driven inflammatory cascades, and disruption of self-tolerance. These adverse effects can severely compromise the already fragile immune landscape in aged individuals ( Figure 2 ).

A major concern is the vicious cycle between immune overload and immune reserve exhaustion, which are tightly interconnected and dialectically unified ( Table 5 ). Specifically, OV therapy triggers acute surges in pro-inflammatory cytokines such as IL-6, type I/II interferons, and TNF, which markedly upregulate Pdcd1 (PD-1) and Cd274 (PD-L1) transcription in T cells, leading to functional overload and subsequent depletion of immune reserves ( 18 , 52 ). Moreover, combinatorial regimens involving T-VEC and chemotherapeutics (e.g., doxorubicin) can further escalate IL-6 levels from ~56 pg/mL to ~170 pg/mL, intensifying this immunological strain ( 53 ).

Elderly individuals inherently exhibit elevated baseline levels of IL-6 and TNF-α, reduced naïve T-cell pools, and increased expression of exhaustion markers (e.g., PD-1, TIM-3), indicative of immunosenescence ( 54 , 55 ). This aging-associated immune state exacerbates the risk of immune overload and exhaustion under OV therapy, contributing to lymphopenia and impaired T-cell metabolism ( 56 – 58 ). Additionally, OV-induced hematopoietic stem cell depletion worsens metabolic dysfunction and deepens immunosuppression ( 19 ).

Conversely, immune exhaustion can also precipitate further immune overload. OV treatment activates robust antiviral T-cell responses and upregulates interferon-stimulated genes (ISGs), fostering a suppressive immune milieu via checkpoint molecule induction. In elderly patients, prior viral exposures contribute to memory T-cell bias, reducing the naïve T-cell repertoire ( 59 – 61 ). OV-induced inflammation disproportionately burdens the remaining unskewed T cells, leading to their numerical expansion but diminished function ( 62 – 64 ). This paradoxical expansion is frequently followed by contraction via activation-induced cell death (AICD) ( 65 , 66 ), culminating in accelerated immune reserve depletion. Moreover, tumor lysis by OVs generates debris accumulation, triggering cholesterol overload in tumor-associated macrophages and impairing their phagocytic capacity, further taxing immune resources ( 67 ).

OV therapy can also induce cytokine release syndrome (CRS), characterized by explosive surges of IL-6 and TNF-α within a short period ( 18 ). CRS represents one of the most life-threatening acute toxicities of OV therapy ( 68 , 69 ). Despite prophylactic use of potent corticosteroids (e.g., dexamethasone) ( 70 ) or localized administration strategies ( 25 ), CRS manifestations such as fever, elevated AST, thrombocytopenia, and treatment interruptions remain common ( 20 ). The self-amplifying “inflammation–immunosuppression cycle” in the elderly, characterized by increased levels of immunosuppressive metabolites such as lactate, further amplifies the severity and long-term consequences of CRS ( 71 – 73 ). However, systematic age-specific incidence data remain lacking, limiting the ability to quantitatively assess the severity and exact frequency of adverse events in elderly patients ( Table 6 ).

Furthermore, OV therapy disrupts immune tolerance in elderly individuals. Rapid lysis of tumor cells releases large quantities of shared self-tumor antigens, which are cross-presented by antigen-presenting cells (APCs), eliciting secondary T/B cell responses against non-target self-epitopes and triggering autoimmune reactions ( 23 , 74 ). Potent activation of dendritic cells and the upregulation of type I IFN and TLR signaling lower the threshold for immune tolerance, promoting bystander activation of autoreactive lymphocytes ( 22 ). Additionally, molecular mimicry between OV components and self-antigens drives T cell–mediated autoimmune cross-reactivity ( 75 ).

Genetically engineered OVs expressing immune modulators such as anti–CTLA-4 further amplify T-cell responses, intensifying autoimmune pathology and impairing immune tolerance ( 21 ). As a result, OV therapy has been associated with various immune-related adverse events (irAEs), including vitiligo, lupus vasculitis, psoriasis, pneumonitis, and encephalitis ( 25 ). These risks are significantly heightened when OVs are combined with immune checkpoint inhibitors, leading to increased rates of grade ≥3 treatment-related adverse events ( 24 ), and underscoring the compounded vulnerability of immune tolerance in aged hosts ( 76 , 77 ).

Table 7 provides a comprehensive overview of the mechanisms, evidence, and clinical data supporting OV-induced disruption of immune self-tolerance.

Discussion

Over the next 5–10 years, the immunological frailty of elderly cancer patients is expected to be progressively overcome ( Table 8 ). Tumor-induced immunosuppression may be alleviated through a range of combination strategies, such as the use of the A2A receptor antagonist ciforadenant in conjunction with anti–PD-L1 therapy ( 78 ), CD73 inhibitors paired with immune checkpoint blockade ( 79 , 80 ), and VEGF-Trap agents that correct dendritic cell differentiation defects ( 81 ). Furthermore, the development of novel drugs is anticipated based on evidence that the PDE5 inhibitor tadalafil effectively reduces MDSC and Treg levels ( 82 ).

Age-related immunosenescence is likely to be addressed by augmenting the quantity and quality of immune cells. Quantitative improvement may be achieved using cytokines such as recombinant human IL-7 to expand naïve and central memory T cells ( 83 ). Qualitative enhancement may involve low-dose mTOR inhibitors to downregulate PD-1 expression in T cells ( 84 ) and pharmacological agents such as metformin to attenuate T cell senescence through multidimensional mechanisms ( 85 ). In addition, reversible sex steroid ablation (SSA) and thymic regeneration approaches are under exploration to restore immune competency ( 85 ), providing a multifaceted strategy to counter immunosenescence.

To interrupt the vicious cycle between immunosuppression and immune exhaustion, standard treatment regimens such as tocilizumab combined with glucocorticoids—commonly used for CRS induced by CAR-T or checkpoint inhibitors—will be expanded ( 68 , 69 ). JAK inhibitors like ruxolitinib, which can rapidly suppress cytokine surges and alleviate CRS, are also being investigated for broader application in immune-related toxicity control ( 86 – 90 ), paving the way for the development of next-generation interventions.

In parallel, the three core immune-related challenges induced by oncolytic virus (OV) therapy in elderly cancer patients will likely be tackled within the coming decade ( Table 9 ). To break the bidirectional vicious cycle of immune overload and immune reserve exhaustion, emerging strategies include pharmacokinetic-based dosing (“controlled-peak” regimens), intratumoral administration to enhance local immune activation and reduce systemic toxicity, and low-dose fractionated schedules that optimize efficacy–safety ratios ( 91 – 93 ). Additional approaches involve enhancing cholesterol efflux and metabolic reprogramming to activate the ApoA1/ABCA1 pathway and improve macrophage phagocytosis and macrophage–T cell synergy ( 67 ), as well as IL-7–mediated expansion of T cell pools and diversification of the TCR repertoire to “replenish immune reserves” ( 83 , 94 , 95 ).

The challenge of cytokine storm (CRS) will be addressed through first-line use of IL-6R blockers such as tocilizumab for rapid symptom relief ( 87 , 89 , 96 , 97 ). For steroid-refractory CRS, IL-1R blockers (e.g., anakinra) and JAK1/2 inhibitors (e.g., ruxolitinib) will be employed to mitigate cytokine levels while preserving antitumor activity ( 86 – 90 ). This comprehensive, multi-tiered control framework is essential for CRS prevention and management.

The disruption of immune tolerance associated with OV-based regimens will be managed using a structured irAE management protocol based on current ICI guidelines. First-line glucocorticoids will serve as foundational therapy, with second-line, organ-specific agents such as infliximab for colitis, mycophenolate mofetil for hepatitis, and IVIG/rituximab for dermatologic and hematologic toxicity ( 8 , 9 ). For cardiotoxicity, the combination of abatacept (CTLA-4-Ig) and ruxolitinib has shown promise in reversing ICI-induced myocarditis ( 98 – 100 ). Drug delivery route optimization—via intratumoral or regional administration when possible—will further reduce systemic exposure and minimize the risk of bystander immune activation ( 101 , 102 ), offering a holistic strategy to restore immune tolerance.

Despite these advancements, the unique immune landscape of elderly cancer patients remains marginalized ( Table 10 ). Due to comorbidities, suboptimal biomarker profiles, and compromised performance status ( 103 ), elderly individuals comprise only 17.7% of early-phase clinical trial participants ( 14 ). Within the context of OV therapy, elderly patients account for 34.4% of immune-related adverse events ( 25 ), and are at heightened risk of severe complications—such as disseminated HSV infection or encephalitis—even with localized treatments like T-VEC ( 26 ).

However, geriatric assessment (GA), a tool proven to reduce severe toxicity and improve outcomes, remains underutilized in routine clinical practice. This oversight leads to insufficient immunological risk assessment, ultimately contributing to elevated rates of adverse events, hospitalizations, treatment non-compliance ( 6 , 104 – 107 ), and even unexpected mortality or treatment discontinuation ( 108 – 110 ).

Therefore, at the clinical level, we recommend establishing a three-tiered frailty-based dosing strategy: standard-dose regimens for mildly frail patients, 25–50% dose reduction for moderately frail patients, and cautious risk–benefit evaluation for severely frail patients. In addition, a CRS early-warning system should be implemented, focusing on three critical markers: IL-6 levels, body temperature fluctuations, and platelet count. For high-risk individuals with a G8 score ≤14, enhanced monitoring protocols should be applied. Moreover, geriatric assessment (GA) should be standardized as a prerequisite for OV treatment in patients aged ≥65 years. In terms of clinical research, elderly patients should comprise ≥30% of enrolled participants, with at least three ongoing trials dedicated to dose optimization in this population. Furthermore, a dedicated OV safety database containing ≥200 elderly cases should be established to quantify age-specific risks and support precision medicine initiatives.

Acknowledgments

This is a short text to acknowledge the contributions of specific colleagues, institutions, or agencies that aided the efforts of the authors.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

J-WW: Conceptualization, Investigation, Validation, Visualization, Writing – original draft. J-HL: Project administration, Supervision, Writing – original draft. Y-LL: Supervision, Writing – review & editing. W-ZX: Supervision, Writing – review & editing. Z-BZ: Project administration, Supervision, Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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