Circadian rhythm-guided cellular therapy in hematologic malignancies: mechanisms, clinical evidence, and optimization strategies.

Introduction

Hematologic malignancies are a group of heterogeneous malignant diseases originating from the hematopoietic and lymphoid systems, including leukemia, lymphoma, multiple myeloma, posing a serious threat to human health due to their high incidence and mortality [ 1 , 2 ]. While traditional treatments such as chemotherapy and radiotherapy are limited by poor targeting, substantial toxicity, and high relapse rates, cellular therapies, including chimeric antigen receptor T cell (CAR-T) therapy and hematopoietic stem cell transplantation (HSCT), have achieved revolutionary success in treating relapsed or refractory hematologic malignancies [ 3 – 6 ].

Circadian rhythms, fundamental physiological oscillator, govern key biological processes including hematopoiesis, immunity, and metabolism [ 7 ]. Emerging evidence indicates that circadian disruption is prevalent in patients with hematologic malignancies and can affect tumor proliferation, immune cell function, and treatment response [ 8 ]. This raises the possibility that circadian rhythm-guided treatment optimization could enhance therapeutic outcomes while minimizing toxicity.

Although the influence of circadian rhythms on cancer biology and treatment response is increasingly recognized, their translational application in hematologic malignancies and cellular therapy remains underexplored. In particular, the links among leukemic clock disruption, immune cell rhythmicity, stem cell transplantation, CAR-T cell function, and clinical chronotherapeutic intervention have been integrated into a unified translational framework in our review (Fig. 1 ). In this review, we summarize current knowledge on the interplay between circadian regulation and hematologic malignancies, with a focus on stem cell transplantation and cellular immunotherapy. We also discuss emerging clinical evidence and practical chronotherapeutic optimization strategies across the cellular therapy workflow, encompassing cell collection, ex vivo manufacturing, infusion timing, and post-treatment supportive care, and highlight circadian phase assessment as a potential foundation for personalized implementation.

Fig. 1 Schematic overview of circadian regulation in hematopoiesis and chronobiology-guided cellular therapy. The hierarchical and translational framework connects the central circadian clock to the optimization of cellular therapies for hematologic malignancies. The suprachiasmatic nucleus (SCN) in the hypothalamus functions as the master clock, synchronizing peripheral clocks in hematopoietic and immune cells to maintain homeostatic regulation of HSCs, T cells, B cells, macrophages, dendritic cells (DCs), and NK cells. In hematologic malignancies, circadian rhythm is disrupted, contributing to leukemogenesis, disease progression, and immune evasion through cell-intrinsic and microenvironmental clock dysregulation. The lower panel depicts a chronobiology-guided cellular therapy workflow (HSCT and CAR-T) aimed at improving anti-tumor responses and reducing toxicity (severe CRS and GVHD risk, inflammation) through four key optimization strategies: (1) evening collection of stem cells to align with peak CD34 + cell mobilization; (2) ex vivo synchronization of therapeutic cells during manufacturing; (3) morning infusion to align with a low-inflammatory host microenvironment; and (4) peri-transplant circadian supportive care to enhance host rhythms. Visualization generated with BioGDP.com [ 9 ]

Biological basis of circadian regulation of hematopoiesis and anti-tumor immunity

The circadian rhythm is an intrinsic, approximately 24-hour oscillatory system conserved across species from bacteria to humans. It maintains temporal homeostasis by regulating diverse physiological processes including gene expression, cell cycle progression, and metabolism [ 7 ]. In mammals, the circadian system is hierarchically organized, with the suprachiasmatic nucleus (SCN) of the hypothalamus serving as the central pacemaker that synchronizes peripheral oscillators in various tissues [ 10 , 11 ].

At the molecular level, interlocked transcriptional-translational feedback loops involving core clock genes—including CLOCK, BMAL1, Period (PER1-3), and Cryptochrome (CRY1-2) [ 12 ], integrate diverse environmental and metabolic stimuli to generate intrinsic 24-hour timing [ 13 ]. In mammals, the two basic helix-loop-helix transcription factors, CLOCK and BMAL1, heterodimerize through their PAS domains and bind to E-box elements, thereby upregulating the transcription of PER1, PER2, CRY1, and CRY2 genes [ 14 – 16 ]. These core clock genes and their regulatory loops lay the foundation for the mutual regulation between circadian rhythm and hematopoietic cells and immune cell function [ 17 , 18 ] (Fig. 2 ).

Fig. 2 Circadian regulation of hematopoietic and immune cells. The mammalian circadian clock is driven by a conserved transcription–translation feedback loop in which CLOCK and BMAL1 heterodimerize and activate the expression of Period (PER1–3) and Cryptochrome (CRY1–2) genes via E-box promoter elements. Once translated, PER and CRY proteins repress CLOCK–BMAL1 activity, thereby establishing a self-sustained ~ 24‑hour oscillation. This molecular clock coordinates rhythmic functions across diverse immune lineages, including hematopoietic stem cell (HSC) mobilization and homing, T‑cell activation and cytokine production, B‑cell maturation and effector differentiation, dendritic cell (DC) trafficking and CD80 expression, macrophage inflammatory and phagocytic activity, and natural killer (NK) cell cytotoxicity. Representative time‑of‑day effects, such as the evening peak in HSC egress and the morning peak in NK cell cytolytic function, highlight how circadian timing temporally organizes immune homeostasis and anti‑tumor immunity. Visualization generated with BioGDP.com [ 9 ]

Hematopoietic stem cells

The circadian clock systematically regulates hematopoietic stem cell (HSC) biology at multilple levels. In a landmark study published in Nature in 2008 [ 19 ], Méndez-Ferrer et al. first demonstrated that HSC release into the bloodstream is governed by circadian oscillations, a seminal finding that established the foundation for this field. They showed that circulating HSCs and their progenitors exhibit robust circadian fluctuations in mice, peaking 5 h after light onset (ZT5) and reaching a nadir 5 h after darkness, driven by rhythmic norepinephrine secretion from the sympathetic nervous system that downregulates CXCL12 in the bone marrow niche. Building on this work, subsequent studies have delineated dual peaks of HSC activity entrained by light–dark transitions: a morning peak (ZT5 in mice) triggered by norepinephrine that promotes egress and differentiation, and a nocturnal peak (ZT17) mediated by melatonin that supports self-renewal and stemness [ 20 ]. Mechanistically, the sympathetic nervous system (SNS)-CXCL12 axis constitutes a core circuit consistent with the original observations of Méndez-Ferrer et al., rhythmic norepinephrine release suppresses CXCL12 in the niche, thereby facilitating HSC mobilization [ 21 ]. Parallel to this, the complement-S1P axis further enhances this process, with circadian complement activation generating C5a, stimulating S1P release and establishing a gradient that guides HSC entry into circulation [ 22 ]. Notably, species-specific timing must be considered for clinical translation: in contrast to nocturnal mice, humans exhibit peak CD34 + HSC levels in the evening [ 23 ], suggesting that evening apheresis may optimize stem cell yield for HSCT in hematological cell therapies.

T cells

As central effectors in CAR-T therapy and HSCT, T-cell trafficking, activation, differentiation, and functional responses are tightly regulated by circadian clocks. Core clock genes, particularly BMAL1, drive diurnal variation in T cell responses to antigen stimulation, with enhanced activation and cytokine secretion at specific times [ 24 ]. For CD8⁺T cells, Per1 and Per2 have rhythmic expression [ 25 , 26 ], and the intrinsic circadian clock modulates their early response to vaccination, as well as the rhythmicity of downstream signaling pathways [ 26 ].

CD4⁺T cells exhibit conserved rhythmic gene expression between mice and humans [ 27 ]. Circadian rhythms have an important role in CD4⁺T differentiation. The circadian clock gene Per1 suppresses Th1 cytokine expression by inhibiting Akt/mTORC1 signaling [ 28 ], thereby shifting the helper T cell subset balance toward Th2 and enhancing antibody secretion during stress responses [ 29 ]. Th17 differentiation is clock-controlled via regulation of key transcription factors [ 30 , 31 ].

Furthermore, lymphocyte-intrinsic clocks and systemic cues like cortisol control their trafficking to lymph nodes, optimizing adaptive immune surveillance [ 32 , 33 ]. Taken together, these observations indicate that circadian timing influences T-cell biology in ways directly relevant to CAR-T manufacturing, in vivo expansion, persistence, and toxicity.

B cells

The molecular clock plays a role in B cell development. Targeted disruption of MOP3 (BMAL1) in mice results in a profound blockade of B cell maturation at the transition from pre-B to immature B cells in the bone marrow, leading to a 50–70% reduction in peripheral mature B cells. Notably, T cell development remains unaffected in MOP3-deficient mice, underscoring the cell-type specificity of circadian regulation within the lymphoid lineage [ 34 ]. Another study found that conditional ablation of BMAL1 reveals that the cell-intrinsic circadian clock is dispensable for B cell differentiation, effector function, and cytokine responses [ 25 ], indicating that daily B cell dynamics are primarily driven by systemic circadian cues rather than cell-autonomous clock activity.

Macrophages

As key innate immune effectors, macrophage is clock-controlled, with BMAL1 serving as a central regulator [ 35 ]. Peritoneal macrophages exhibit self-sustained oscillations in core clock gene expression, driving rhythmic immune-related gene expression [ 36 ]. BMAL1 regulates inflammation via NRF2-mediated IL-1β control [ 37 ], and modulates TLR4 responses through enhancer RNA transcription [ 38 ]. Additionally, BMAL1 negatively regulates macrophage motility and phagocytosis [ 35 ]. Targeting macrophage circadian rhythms may thus offer a strategy to modulate inflammation and anti-tumor immunity in the context of cellular therapy.

Dendritic cells

Dendritic cells (DCs), key antigen-presenting cells, exhibit robust circadian rhythms governed by BMAL1 and niche cues. Diurnal migration peaks during the late light phase (ZT7–9 in mice) [ 39 ]. Preclinical studies show tumor growth is significantly suppressed when implanted at ZT9 (peak DC function) versus ZT21 (trough). Mechanistically, BMAL1 regulates rhythmic CD80 expression in DCs (peaking at ZT8), enhancing DC migration to tumor-draining lymph nodes and CD8⁺ T cell activation. DC-specific BMAL1 ablation eliminates this time-dependent anti-tumor effect [ 40 ]. These findings suggest that restoring or aligning DC circadian rhythm could improve the efficacy of therapies like CAR-T and HSCT.

NK cells

In healthy individuals, NK cell cytotoxicity peaks at morning and reaches its nadir at midnight [ 41 ]. Circadian rhythms modulate NK cell cytokine release and cytolytic activity [ 42 ], with peak cytotoxicity coinciding with higher expression of perforin and granzyme B, and is controlled by core clock genes [ 43 , 44 ]. These findings suggest that timing the collection and infusion of adoptive NK cells to align with their functional peaks may optimize therapeutic efficacy.

Circadian disruption and regulatory mechanisms in hematologic malignancies

Circadian disruption is common in hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, which are summarized in Table 1 . Key mechanisms involve: (1) mutations or dysregulation of core clock genes impairing feedback loops; (2) epigenetic alterations (DNA methylation, histone modification) silencing clock genes; (3) dysregulated metabolic and signaling pathways (JAK/STAT, PI3K/Akt, MYC); (4) impaired immune function; and (5) environmental factors (shift work, light exposure, irregular sleep) exacerbating circadian misalignment and promoting tumor progression. Across these malignancies, disruption converges on shared themes, including repression of clock genes and deregulated signaling. However, the functional consequence of specific clock components can be context-dependent, underscoring the need for disease-specific profiling.

Table 1 Circadian dysregulation in hematologic malignancies Tumor type Clock gene expression /functional alteration Biological role and mechanism References AML BMAL1 hypermethylation or overexpression Linked to poor prognosis; blocks ferroptosis and promotes chemoresistance. [ 45 – 48 ] AML PER3 upregulation Associated with favorable outcome. [ 49 ] AML CLOCK and BMAL1 dysregulation in LSCs required for LSC maintenance. [ 50 ] AML Circadian/dietary intervention Reduces progression [ 51 ] ALL CLOCK/BMAL1 knockdown in T-ALL Suppresses leukemia-initiating cell activity via IL20RB-JAK/STAT signaling. [ 52 ] ALL Sleep-wake and activity rhythm disruption Associated with fatigue in pediatric ALL [ 53 , 54 ] CML PER1-3, CRY1-2, and BMAL1 downregulation Indicates global clock disruption and is partly reversible in remission. [ 55 ] CML PER2 downregulation Inhibiting proliferation and inducing apoptosis. [ 56 , 57 ] CML hPER3 hypermethylation; loss of BMAL1 oscillation Associated with disease progression; Sirt1 inhibition restores BMAL1 rhythmicity. [ 58 , 59 ] CLL BMAL1, PER1, and PER2 downregulation Reflects fundamental circadian disruption. [ 60 ] CLL High CRY1 expression/methylation; altered PER2:CRY1 ratio Correlates with poor prognosis and adverse outcome. [ 60 – 62 ] CLL Long-term night shift exposure Increases risk and exacerbates clock disruption. [ 63 ] HL TNFα-clock crosstalk Regulates lymphoma cell proliferation and migration. [ 64 ] Burkitt lymphoma PERK-miR-211-mediated BMAL1/CLOCK suppression Promotes tumor cell survival. [ 65 ] DLBCL PER3 polymorphism; PER2 deregulation PER3 variation is associated with improved survival [ 66 , 67 ] NHL CRY2 polymorphisms; night work Associated with increased NHL risk. [ 68 , 69 ] MM GLYR1-PER3 axis promote MM proliferation. [ 70 ] MM REV-ERB agonist SR9009 Suppresses GRP78-dependent autophagy and synergizes with proteasome inhibitors. [ 71 ] MM Programmed illumination Reduces depression severity. [ 72 ] MM Circadian variation of serum erythropoietin and beta2-microglobulin Linked to disease activity and monitoring. [ 73 , 74 ]

Acute myeloid leukemia

Acute myeloid leukemia ( AML) exhibits significant circadian dysregulation. BMAL1 expression is context-dependent: some studies report epigenetic silencing via promoter hypermethylation [ 45 ], while others show elevated BMAL1 associated with poor prognosis [ 46 ]. On the other side, PER3 upregulation correlates with better outcomes [ 49 ]. Clock gene dysregulation differs between leukemia stem cells (LSCs) and differentiated blasts, with core genes essential for LSC maintenance [ 50 ].

Mechanistically, BMAL1 promotes AML progression by inhibiting ferroptosis via following pathways: EBF3/ALOX15, HMGB1-GPX4, and IKZF2/ASAH2 axes [ 46 – 48 ]. Meanwhile, targeting BMAL1 can reverse drug resistance of AML cells and enhance chemosensitivity [ 46 ]. In addition, feasible dietary and circadian interventions can reduce the in vivo progression of FLT3-ITD-positive AML [ 51 ]. These studies collectively reveal the core role of circadian rhythm abnormalities in the occurrence and development of AML.

Acute lymphoblastic leukemia

In T-acute lymphoblastic leukemia (ALL), knockdown of core clock genes CLOCK and BMAL1 can significantly inhibit the in vitro growth and in vivo activity of leukemia-initiating cells (LICs) via IL20RB-JAK/STAT signaling [ 52 ]. Pediatric ALL patients exhibit disrupted sleep-wake rhythms linked to fatigue, which can be exacerbated by dexamethasone therapy [ 53 , 54 ]. These findings underscore the importance of circadian monitoring and supportive care in ALL.

Chronic myeloid leukemia

Chronic myeloid leukemia ( CML) is characterized by universal downregulation of core clock genes (PER1-3, CRY1-2, BMAL1), partially reversible upon remission [ 55 ]. Among these genes, PER2 acts as a tumor suppressor, inhibiting proliferation and inducing apoptosis in CML cells [ 56 , 57 ]. Epigenetic silencing via hPER3 promoter hypermethylation correlates with disease progression [ 58 ]. Additionally, the circadian rhythm oscillation is completely lost in peripheral blood mononuclear cells (PBMCs) of CML patients, and Sirt1 inhibition partially restores BMAL1 oscillation, suggesting therapeutic potential [ 59 ]. Collectively, these studies provide important insights into the role of circadian rhythm in CML pathogenesis and potential therapeutic strategies.

Chronic lymphocytic leukemia

In chronic lymphocytic leukemia ( CLL), circadian rhythm dysregulation is a fundamental feature. BMAL1, PER1, and PER2 often downregulated [ 60 ], while high CRY1 expression and promoter methylation of CRY1 correlates with poor prognosis [ 60 , 61 ]. Additionally, the PER2:CRY1 ratio predicts worse outcomes [ 62 ]. Long-term night shift work increases CLL risk and exacerbates clock disruption [ 63 ]. Thus, clock gene expression profiles, particularly CRY1 and the PER2:CRY1 ratio, may serve as prognostic biomarkers and potential indicators for chronobiology-informed intervention.

Lymphoma

In lymphoma, circadian rhythm dysregulation is closely associated with disease occurrence, progression, and prognosis, involving multiple subtypes including diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and large B-cell lymphoma. In HL, TNFα-clock crosstalk regulates proliferation and migration [ 64 ]. Besides, in Burkitt’s lymphoma, the PERK-miR-211 axis suppresses Bmal1/Clock, promoting survival [ 65 ]. In DLBCL, PER3 polymorphism correlates with improved survival [ 66 ], and PER2 is significantly deregulated [ 67 ]. In NHL, CRY2 gene polymorphisms are associated with increased NHL risk [ 68 ], and night work predisposes to NHL [ 69 ]. Collectively, these findings provide insights into chronotherapeutic strategies for clinical practice.

Multiple myeloma

In multiple myeloma (MM), circadian rhythm dysfunction manifests through diverse mechanisms involving molecular regulation, therapeutic interventions, and clinical biomarkers. At the molecular level, GLYR1 regulates PER3 to promote MM proliferation [ 70 ]. Preclinically, Rui Wang et al. found that SR9009, a REV-ERB agonist, suppresses GRP78-dependent autophagy and synergizes with proteasome inhibitors [ 71 ]. Clinically, programmed illumination during autologous transplantation reduces depression severity [ 72 ]. Additionally, Serum erythropoietin and β2-microglobulin exhibit circadian variations linked to disease activity [ 73 , 74 ]. Collectively, these studies provide important insights for molecular targeting therapy, clinical supportive care and disease monitoring.

Chronotherapeutic foundations in oncology

Chronotherapy, the practice of tailoring treatment administration to the body’s endogenous circadian rhythms, has decades of preclinical and clinical validation in oncology, particularly in chemotherapy [ 75 , 76 ]. Early work by Francis Lévi and colleagues first showed the feasibility and antitumor activity of circadian-timed oxaliplatin, fluorouracil, and leucovorin regimens in metastatic colorectal cancer, initially in phase II and subsequently in multicenter studies [ 77 , 78 ]. Randomized evidence then consolidated this framework, demonstrating that chronomodulated delivery could improve tolerability and, in selected settings, antitumor efficacy compared with constant-rate infusion [ 79 , 80 ]. In parallel, mechanistic studies from Lévi and Schibler helped define the biological basis of chronotherapy by linking treatment responses to hierarchical circadian control of cellular physiology, metabolism, and drug handling [ 81 ], while experimental work further showed that disruption of circadian coordination could itself promote malignant growth [ 82 ]. These findings established biological timing as a clinically actionable variable rather than a merely descriptive phenomenon.

Importantly, subsequent studies also demonstrated that chronotherapy cannot be reduced to a fixed clock-time approach. Instead, its clinical benefit appears to depend on host-specific biological variables. In metastatic colorectal cancer, sex was shown to moderate survival effect of chronomodulated chemotherapy [ 83 ], and the robustness of the circadian rest–activity rhythm independently correlated with survival, tumor response, symptom burden, and quality of life [ 84 ]. Consistent with this shift toward personalization, molecular clock–based modeling studies suggested that optimal treatment timing may be predicted from host circadian transcriptional states rather than inferred solely from external clock time [ 85 ]. These developments are summarized in a recent review by Lévi and colleagues that emphasizes sex-specific and personalized chronotherapy as the current direction of the field [ 86 ].

More recent evidence has reinforced the clinical relevance of this framework while also highlighting substantial heterogeneity across tumor types, regimens, and study designs [ 76 ]. In this context, extending chronobiological principles to immunotherapy and cellular therapy should be viewed not as a new departure, but as a logical next step: from timing drug delivery alone toward optimizing the timing of immune engagement, host tolerance, and potentially the functional state of living therapeutic products [ 87 ]. Cellular therapy is a particularly instructive setting because timing may influence not only host tolerance and tumor susceptibility, but also the functional quality of the therapeutic product itself. Processes such as leukapheresis, ex vivo activation and expansion, conditioning, infusion, and post-infusion immune recovery are biologically dynamic and potentially circadian-sensitive. Applying chronobiology to CAR-T therapy, HSCT, and other cellular approaches therefore represents a direct extension of the broader chronotherapy paradigm into the era of living drugs and precision immuno-oncology (Fig. 3 ).

Fig. 3 The paradigm shift in cancer chronotherapy: from fixed-time delivery to personalized living therapeutics. This schematic illustrates the evolution of cancer chronotherapy across three interconnected stages. The classical approach relies on the central suprachiasmatic nucleus (SCN) clock to approximate population-level 24-hour rhythms and administers standard chemotherapeutic agents at a fixed clock-time that coincides with peak drug tolerability, aiming to minimize systemic toxicity. The personalized strategy moves beyond universal timing by integrating host-specific biological variables, including sex dimorphism, actigraphy-derived rest-activity rhythms, and individual circadian transcriptional profiles, to dynamically predict an optimal therapeutic window tailored to the patient’s unique circadian phenotype. The emerging paradigm of chrono-cellular therapy extends these principles to “living drugs”. Because these products are biologically dynamic and circadian-sensitive, the entire treatment workflow: from initial leukapheresis and ex vivo expansion through to final infusion, which is considered a potential target for circadian optimization, with the goal of maximizing in vivo immune engagement and engraftment efficacy. Visualization generated with BioGDP.com [ 9 ]

Circadian effects on cellular therapies of hematologic malignancies

Hematopoietic stem cell transplantation

HSCT outcomes are significantly influenced by circadian rhythm, with effects at multiple stages from donor mobilization to post-transplant recovery.

Clinical associations between infusion time and HSCT outcomes

A series of landmark clinical retrospective studies conducted by the University of Science and Technology of China team have systematically clarified the clinical association between circadian rhythm and HSCT outcomes, covering both allogeneic peripheral blood HSCT and umbilical cord blood transplantation (UCBT) [ 88 , 89 ]. The team’s initial clinical research found that in allogeneic peripheral blood HSCT, recipients in the early-infused group (before 2:00 PM) were correlated with lower acute graft versus host disease (aGVHD) incidence, 3-year transplant-related mortality, and higher relapse-free survival than those in the late-infused group (after 2:00 PM). A subsequent external validation cohort multicenter study confirmed that infusion before 2:00 PM was associated with reduced aGVHD incidence [ 88 ].

Building on these findings, a targeted clinical retrospective study focusing on UCBT analyzed 434 patients who received unrelated UCBT. Patients who received cord blood infusion before 9:40 AM exhibited a correlation with markedly lower incidence of severe (III-IV grade) aGVHD (16.0%) compared with those who received late infusion (27.9%, P = 0.004), while the difference in II-IV grade aGVHD was not statistically significant. This observational finding highlights that circadian timing exerts a more pronounced protective effect against severe aGVHD in UCBT [ 89 ].

A validation cohort study at Geneva University Hospitals between 2015 and 2024 further verified these findings: the study conducted a multi-center validation with 368 allogeneic HSCT patients, confirming that earlier graft infusion (before 11:00 ) was consistently associated with reduced non-relapse mortality and improved long-term survival [ 90 ], which further validated the regulatory role of circadian rhythm in HSCT outcomes and strengthened the clinical evidence for time optimization of HSCT infusion.

Two Phase III randomized controlled trials are currently underway to provide high-quality, prospective evidence: NCT06294678 compares outcomes in patients with malignant hematologic diseases receiving allogeneic HSCT between 11:30–12:30 AM and 3:30–5:30 PM, while NCT06294691 focuses on patients with non-malignant hematologic diseases using the same time windows. These prospective trials are critical to transform current associative findings into causal clinical conclusions.

Biological mechanisms linking circadian phase to HSCT efficacy

Mechanistically, the protective effect of early infusion in peripheral blood HSCT was linked to the circadian fluctuation of the pro-inflammatory cytokine IL-1α in recipients: IL-1α levels were lowest in the morning/early afternoon, creating a low-inflammatory microenvironment that favors HSC engraftment and reduces excessive immune activation [ 88 ] .

In UCBT, the study identified soluble CD26 (sCD26, DPP4) as the key molecular mediator linking circadian rhythm to transplantation outcomes. sCD26 exhibited statistically significant circadian fluctuation in patients’ serum: levels were lowest in the early morning (7:00 AM), gradually increased throughout the day, and peaked in the afternoon (4:00 PM), a pattern directly regulated by the core clock gene BMAL1. Elevated sCD26 levels promote the activation of pro-inflammatory pathways and enhance immune rejection responses, thereby increasing the risk of severe aGVHD after late infusion [ 89 ]. Notably, the study also proposed a clinically actionable intervention strategy: inhibiting sCD26 activity with DPP-4 inhibitors (e.g., sitagliptin) could mitigate the severity of aGVHD in mice receiving late UCBT [ 89 ].

Critically, these finding bridges the gap between circadian timing optimization and targeted pharmacologic intervention in HSCT, forming a complete evidence chain from timing effect to mechanistic verification. Compared with CAR-T therapy, HSCT may provide an even broader window for chronobiological optimization, as circadian influences act at multiple stages: donor mobilization, stem cell harvesting, conditioning, graft infusion, homing, engraftment, immune reconstitution, and GVHD.

CAR-T cell therapy

As a core cellular therapy for relapsed and refractory hematologic malignancies, CAR-T cell therapy has significant individual differences in efficacy and safety, with circadian rhythm being an important influencing factor. Several large-sample, multi-center studies have explored the association between diurnal differences in CAR-T infusion time and clinical outcomes, with three key studies providing complementary and conflicting evidence to guide clinical practice.

Clinical associations between infusion time and CAR-T outcomes

A large-sample observational study of 715 patients receiving CAR-T therapy analyzed the correlation between intraday infusion time and treatment effectiveness. It found that early morning (7:00–9:00 AM) infusion was associated with significantly higher 1-year PFS, ORR, and lower CRS incidence. Early morning infusion also correlated with better CAR-T expansion, more stable core clock gene (BMAL1, PER2, CRY1) expression, and regular inflammatory factor (IL-2, IFN-γ) secretion, suggesting a potential regulatory correlation between circadian rhythm and CAR-T function [ 91 ].

A multi-center retrospective analysis of 1052 LBCL patients receiving CD19-targeted CAR-T therapy divided infusion time into early (< 12:00 AM) and late (≥ 12:00 AM) groups. The early group had a higher 1-year PFS (51.4% vs. 35.2%), with a 11% increased PFS risk per hour delay (HR = 1.11, 95% CI: 1.03–1.20; P = 0.004), as well as lower recurrence and higher ORR/CR within 100 days (no significant difference in ≥ 2 CRS/ICANS). Late infusion was correlated with severe inflammation and poor CAR-T expansion, providing observational clues for a potential time-dependent pattern in LBCL [ 92 ].

In contrast, a retrospective study of 584 Australian LBCL patients found no significant difference in PFS/OS between morning and afternoon infusion (HR for PFS = 0.90, 95%CI: 0.71–1.16, P = 0.42), despite a higher CR rate in the afternoon (71% vs. 61%). Sensitivity analysis confirmed no association between infusion time and outcomes. Researchers attributed prior positive findings to confounding factors (e.g., better baseline status in morning patients), suggesting circadian rhythm may exert limited clinical impacts on CAR-T outcomes under certain clinical conditions [ 93 ].

Although the first two studies suggest a benefit of morning CAR-T infusion, the interpretation remains cautious because infusion clock time may not accurately reflect either tumor circadian phase or the biological fitness of the infused product. The conflicting results across these studies necessitate a thorough analysis of methodological differences and potential confounders. The first study [ 91 ] included a mixed cohort of 715 patients with various hematological malignancies, while the latter two [ 92 , 93 ] focused exclusively on LBCL patients, which might lead to different results due to divergence in disease biology. Additionally, the sample sizes varied (715 vs. 1052 vs. 584), and populations were from different regions (with the third study was restricted to Australian patients), which could introduce regional differences in clinical practice (e.g., bridging therapy strategies, supportive care protocols) that might confound the association between infusion time and outcomes. Second, differences in baseline disease characteristics and prior treatment history among the study populations may also contribute to the conflicting results. For instance, the proportion of patients with high tumor burden, advanced stage, or prior autologous stem cell transplantation may differ across studies, and these factors are known to affect CAR-T therapy outcomes independently [ 94 , 95 ]. Moreover, variability in CAR-T manufacturing (vector type, T cell subset selection, production protocols) can alter cell quality and function [ 96 , 97 ], potentially interacting with infusion timing to affect clinical results. Unfortunately, detailed manufacturing data were incompletely reported, hindering assessment of this impact. Furthermore, selection bias and center-specific workflow may also confound the observed associations. For example, in clinical practice, patients with better performance status or more stable disease are often scheduled for early morning infusion, while those with more severe or unstable disease receive later infusions. patients with better performance status or more stable disease are often scheduled for early morning infusion, while those with more severe or unstable disease receive later infusions.

In summary, although the first two studies suggest a potential benefit of early morning CAR-T infusion, the contradictory findings from the third study highlight the need for caution. The methodological differences among the three studies, including variations in patient selection, baseline disease characteristics, prior treatments, and regional clinical practices, as well as the inherent limitation of infusion clock time as a surrogate for biological circadian phase, may all contribute to the discrepancies. Therefore, the currently available evidence supports a possible association between infusion timing and CAR-T outcomes in some settings, but it does not establish causality or justify a uniform timing recommendation for all patients. Large prospective studies with predefined timing protocols and direct assessment of circadian phase are needed before circadian-guided infusion can be implemented in routine practice. These trials should incorporate assessments of individual biological circadian phase (monitoring core clock gene expression or melatonin levels) rather than relying solely on clock time, and should control for potential confounding factors such as chronotype, disease-related circadian dysregulation, and CAR-T production variability. These studies will determine whether timing infusions according to biological circadian phase can genuinely improve outcomes and establish a scientific basis for personalized CAR-T strategies.

Biological mechanisms linking circadian phase to CAR-T efficacy

Notably, a pivotal study published in Cell in 2024 clarified the intrinsic circadian regulatory mechanism of CD8 + T cells, the core effector component of CAR-T therapy, providing a key theoretical basis for the circadian optimization of CAR-T therapy [ 98 ]. Specifically, in murine diffuse large B cell lymphoma model, CD8 + CAR-T cells showed the strongest anti-tumor activity at night (corresponding to the active phase of nocturnal mice), while the weakest activity in the morning, which is consistent with the clinical findings of the first two CAR-T studies that early morning infusion is associated with better efficacy. Mechanistically, the study found the endogenous circadian clock of CD8 + CAR-T cells themselves regulates their proliferation, activation, and cytotoxicity; on the other hand, the circadian clock of endothelial cells in the tumor microenvironment regulates the rhythmic expression of adhesion molecules, thereby affecting the infiltration of CD8 + CAR-T cells into tumor tissues. Notably, the immune checkpoint gene Pdcd1 (encoding PD-1) exhibits rhythmic expression regulated by BMAL1 and PER1/PER2, peaking at ZT1 and bottoming at ZT13, which directly affects the responsiveness of CAR-T cells to immunotherapy.

This preclinical study offers a biologically plausible hypothesis linking circadian phase to CAR-T cell function and may partly explain why earlier infusion was associated with improved outcomes in some retrospective cohorts. Nevertheless, it should not be taken as definitive evidence that infusion timing causally determines clinical benefit. The discordant findings across available retrospective studies indicate that any timing effect is likely context-dependent and may be modified by disease subtype, tumor burden, host circadian phenotype, clock-gene expression, inflammatory state, and the degree of circadian disruption within the tumor microenvironment. Future translational studies should therefore combine mechanistic experiments with prospective infusion-timing protocols, longitudinal immune monitoring, and direct measurement of patient circadian phase to define when and for whom circadian-guided CAR-T delivery is beneficial.

Overall, the inconsistent results may be related to the differences in the circadian phenotypes of the study populations, the expression levels of core clock genes, or the degree of tumor microenvironment disorder, which need to be further verified by prospective studies. Future studies should incorporate prospective timing protocols, longitudinal immune monitoring, and direct assessment of patient circadian phase.

Emerging cellular therapies

While CAR-T and HSCT represent the most extensively studied cellular therapies in the context of circadian biology, emerging evidence suggests that other cellular therapeutic modalities are also subject to circadian regulation, with important implications for treatment optimization.

NK cells are critical effectors of innate anti-tumor immunity and are increasingly utilized in adoptive cellular therapy for hematologic malignancies. As detailed in Sect. “NK cells”, the circadian control of NK cell cytotoxicity [ 41 , 43 , 44 ]. These findings have direct therapeutic implications for adoptive NK cell therapy in hematologic malignancies. Similarly, the circadian control of DC migration and function [ 39 , 40 ], suggests that timing could be leveraged to improve DC-based vaccines.

Chronotherapeutic optimization strategies

In hematologic cellular therapy, chronotherapeutic optimization should extend beyond infusion timing to incorporate circadian principles across the entire therapeutic workflow—encompassing cell collection, ex vivo manufacturing, infusion scheduling, and post-treatment supportive care. This integrated framework is especially pertinent in hematologic malignancies, where both malignant cells and immune effector cells are under strong circadian control [ 99 , 100 ] (Fig. 4 ).

Fig. 4 Circadian rhythm-guided optimization of cell infusion and peri-infusion management in hematologic malignancies. This schematic outlines chronotherapeutic opportunities integrated throughout the peri-infusion continuum: from initial patient assessment to post-infusion supportive care. Optimization strategies include timed leukapheresis to enhance HSC or T-cell fitness; ex vivo circadian synchronization; chrono-conditioning; infusion timing aligned with a permissive host microenvironment; and post-infusion light/sleep management. Together, these circadian-guided interventions offer a practical framework to improve engraftment, enhance therapeutic efficacy, mitigate toxicity, and optimize long-term outcomes in cellular therapy for hematologic malignancies. Visualization generated with BioGDP.com [ 9 ]

Timing of cell collection

The timing of cell collection may affect both the quantity and functional state of harvested cells. Hematopoietic stem and progenitor cell trafficking is regulated by circadian signals within the bone marrow niche, and immune cells also exhibit time-of-day variation in distribution, activation state, migratory capacity, and effector potential [ 20 , 32 ]. In the context of HSCT, consistent clinical evidence demonstrates that human CD34⁺ hematopoietic stem cells exhibit a clear evening peak in mobilization, and evening-performed leukapheresis effectively increases total stem cell yield while enhancing the stemness of harvested HSCs, thereby facilitating subsequent engraftment and hematopoietic reconstitution [ 100 ]. In contrast, the circadian optimization of leukapheresis for CAR‑T cell therapy remains largely underexplored. Current preclinical evidence indicates that T‑cell activation, differentiation, and memory phenotype conversion are tightly regulated by the circadian clock. These observations raise the possibility that stem cell collection or leukapheresis performed at biologically favorable times may improve cell yield or cellular fitness. Although this concept remains insufficiently validated in prospective clinical studies, it represents a plausible and testable chronotherapeutic strategy in both transplantation and immune cell–based therapy.

Ex vivo manufacturing synchronization

Standard manufacturing protocols do not currently account for circadian biology. In principle, temporal standardization of key manufacturing steps, synchronization of cellular clocks, or pharmacologic modulation of circadian pathways could improve cellular fitness, persistence, or antitumor activity [ 101 ]. At present, however, these approaches remain largely preclinical and require further mechanistic and translational validation before routine clinical implementation.

Timing of infusion

Infusion timing represents the most clinically advanced and evidence-based chronotherapeutic strategy. Current retrospective clinical data demonstrate associative trends supporting potential benefits of morning infusion for HSCT and CAR-T, but these observational findings cannot confirm definite causal therapeutic advantages [ 88 – 92 ]. The underlying rationale is to align infusion with a host microenvironment that is permissive for engraftment while minimizing the risk of excessive inflammation and severe acute GVHD. Although the current evidence is heterogeneous and includes retrospective analyses, these studies support the concept that treatment efficacy and toxicity may depend not only on product characteristics but also on the circadian state of both the infused cells and the recipient.

Circadian supportive care

Light-based interventions, such as programmed environmental illumination, have been shown to improve mood and quality of life in hospitalized patients [ 72 , 102 ]. Therefore, interventions such as environmental light management, sleep preservation, and time-sensitive monitoring of inflammatory complications may represent simple but clinically relevant adjuncts to cellular therapy. Such measures may be particularly important after HSCT or CAR-T therapy, when immune reconstitution, cytokine dynamics, and host vulnerability are highly time-sensitive.

Clinical assessment of circadian phase

For personalized chronotherapy, treatment timing should ideally be aligned with a patient’s internal circadian phase rather than relying solely on external clock time [ 103 , 104 ]. In clinical practice, circadian phase can be assessed using several complementary approaches, including dim light melatonin onset (DLMO), cortisol rhythmicity, actigraphy, peripheral clock gene expression, and chronotype questionnaires [ 105 – 109 ].

DLMO is among the most well-established markers of central circadian timing; however, its clinical utility is limited by the requirement for controlled dim-light conditions and repeated evening sampling [ 110 ]. Cortisol measurement is more accessible and can be integrated into routine blood sampling, but it is strongly influenced by stress, inflammation, infection, and glucocorticoid exposure [ 111 ]. Actigraphy offers a practical, low-burden method for longitudinal assessment of rest-activity rhythms, although it reflects behavioral rhythmicity rather than directly measuring endogenous circadian phase [ 112 ]. Peripheral clock gene profiling is particularly attractive in hematologic malignancies, as blood-based sampling is feasible and closely linked to immune and hematopoietic biology; nevertheless, this approach has not yet been standardized for routine clinical use [ 108 , 113 ]. Chronotype questionnaires may serve as simple screening tools, but their precision is limited when used alone [ 109 , 114 ].

In practice, a tiered strategy is likely the most feasible approach. Low-burden methods, such as sleep history, chronotype assessment, and actigraphy can be used for initial circadian phenotyping, whereas DLMO, cortisol profiling, or peripheral clock gene assays may be reserved for prospective trials or selected biomarker-driven settings. Such a strategy could support individualized optimization of cell collection, infusion timing, and post-treatment monitoring. Candidate methods for circadian phase assessment and their potential applications are summarized in Table 2 .

Table 2 Candidate methods for circadian phase assessment in hematologic cellular therapy Method What it reflects Advantages Limitations Potential use DLMO Central circadian phase Most established marker of internal circadian phase [ 105 ] Requires dim light and evening sampling; limited practicality [ 110 ] Timing cell collection or infusion Cortisol rhythm Endocrine circadian timing Easy to measure; can use routine samples [ 106 , 111 ] Affected by stress, inflammation, infection, and steroids [ 106 ] Assess host rhythmicity before or after therapy Actigraphy Rest-activity rhythm and sleep timing Non-invasive, low burden, suitable for longitudinal use [ 107 ] Indirect measure; influenced by inactivity and hospitalization [ 112 ] Monitor rhythm disruption around therapy Peripheral clock gene expression Molecular clock status Mechanistically informative; blood-based [ 108 , 113 ] Not standardized; affected by treatment and inflammation [ 113 ] Biomarker studies in HSCT, CAR-T, NK-cell therapy Chronotype questionnaire Behavioral circadian preference Simple and inexpensive [ 109 ] Subjective; low precision alone [ 114 ] Initial patient stratification

Conclusion and perspectives

This review highlights the intricate interplay between circadian rhythms, hematologic malignancies, and cellular therapies. Core clock genes are master regulators of hematopoietic and immune homeostasis, and their disruption actively contributes to leukemogenesis, immune evasion, and treatment resistance. While HSCT and CAR-T therapy have transformed hematologic oncology, their efficacy and toxicity are modulated by circadian biology, with current clinical evidence predominantly consisting of retrospective associations rather than validated causal conclusions, and the translation of basic research to clinical practice is still in progress.

Future research should prioritize: (1) high-quality prospective clinical trials to define optimal timing for cell collection, processing, and infusion; (2) further exploration of the molecular mechanisms underlying circadian regulation in hematologic malignancies is required to identify circadian biomarkers and therapeutic targets; (3) the development of personalized chronotherapeutic strategies is essential and should be based on individual circadian phenotypes, molecular biomarkers, and disease characteristics. In particular, future studies should evaluate clinically feasible approaches for circadian phase assessment, including dim light melatonin onset, cortisol rhythmicity, actigraphy-based rest-activity monitoring, and peripheral clock gene expression profiling, and determine how these measures can be incorporated into treatment scheduling algorithms for HSCT, CAR-T, and other emerging cellular therapies; and (4) ex vivo circadian synchronization of therapeutic cells and pharmacological clock modulation to enhance cellular therapy products.

In conclusion, circadian rhythm represents a promising yet underutilized dimension for optimizing hematologic cellular therapy. Integrating biological timing into treatment design has the potential to improve engraftment, enhance antitumor efficacy, reduce toxicity, and enable more personalized scheduling. As mechanistic insights and clinical evidence accumulate, circadian-guided strategies may become an integral component of precision medicine for hematologic malignancies.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

Figures in this review was created with BioGDP.com [ 9 ].

Author contributions

YT: Writing – original draft, Investigation. XZ: Supervision, Writing – review & editing. AL: Supervision, Writing – review & editing. All authors contributed to the article and approved the submitted version.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This review is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors; it does not require the approval of the independent ethics committee.

Competing interests

The authors declare no competing interests.

Abbreviations

Acute lymphoblastic leukemia

Acute myeloid leukemia

Acute graft versus host disease

Chimeric antigen receptor T cell

Chronic lymphocytic leukemia

Chronic myeloid leukemia

Dendritic cells

Diffuse large B-cell lymphoma

Dim light melatonin onset

Hematopoietic stem cell

Hematopoietic stem cell transplantation

Hodgkin lymphoma

Multiple myeloma

Non-Hodgkin lymphoma

Suprachiasmatic nucleus

Umbilical cord blood transplantation

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