Beyond the calendar: A narrative review on chronobiological drivers of prognosis in resectable NSCLC

Seasonal vulnerability and the Lewis lung model

The impact of seasonality on NSCLC progression has been demonstrated in prior experimental oncology studies. Specifically, studies on Lewis lung carcinoma model have revealed a significant circannual rhythm in metastatic potential.^5,15,16 The formation of pulmonary metastases exhibits a clear acrophase, or peak activity, coinciding with the summer solstice. While derived from experimental models, these findings are conceptually consistent with clinical observations suggesting a period of increased biological vulnerability during the warmer months. ¹⁶

This “seasonal window” of aggressiveness may be closely associated with fluctuations in immune cell populations. In fact, some experimental data have reported that T-cell subsets (specifically CD3+ and CD4+ lymphocytes) undergo a dramatic reduction during the spring-summer period. ¹⁷ Conversely, a significant increase in CD3+ populations is observed during the winter months. This seasonal effect on CD4 (and inversion of the CD4/CD8 ratio) suggests a state of “relative immunodeficiency” during the summer. ¹⁷ These observations suggest that immune competence may vary across the year, potentially contributing to temporal heterogeneity in host–tumor interactions.

Immune cell trafficking and the pulmonary microenvironment

On a circadian scale, leukocyte trafficking between the bone marrow, blood, and peripheral tissues is regulated by the rhythmic expression of adhesion molecules and chemokines.^2,18-20 The cytolytic activity of Natural Killer (NK) cells and the proliferative response of T-lymphocytes follow a precise 24-hour cycle, modulated by the autonomic nervous system and glucocorticoid signaling.^2,17 In the lung, which serves as a major reservoir for marginated granulocytes and lymphocytes, the timing of surgery may coincide with either a “pro-inflammatory” or “immunosuppressive” phase of this cycle, a balance further modulated by seasonal and environmental factors that influence systemic immune tone.^21,22 Chronic chronodisruption leads to a “flat” immune rhythm, characterized by diminished NK cell infiltration and an accumulation of myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment.^5,23

The sun-Vitamin D-VDR axis

The most potent environmental Zeitgeber (time-giver) for circannual rhythms is solar radiation, which governs the systemic levels of Vitamin D. Beyond its role in bone homeostasis, 25-hydroxyvitamin D [25(OH)D] acts as a critical immunomodulator in NSCLC.^9,18,19,24 The Vitamin D receptor (VDR) is widely expressed in both bronchial epithelial cells and tumor-infiltrating lymphocytes. This evidence suggests a possible bridge between the environment and the tumor microenvironment. In the literature, some authors reported that patients with higher circulating Vitamin D levels before surgery had significantly improved recurrence-free survival (RFS), with a reduction in recurrence risk of approximately 18-20% compared with deficient cohorts.^9,18,19,21

This protective effect is further modulated by genetic polymorphisms in the VDR gene, such as the FokI and BsmI variants, which can either enhance or impair anti-proliferative signaling.^18,19 Furthermore, the “Lag-Phase” theory suggests that the peak in Vitamin D synthesis during late summer may provide a protective immunological “buffer,” manifesting as improved outcomes for patients treated in the subsequent autumn months.^9,21,25

The northern latitude model: The summer benefit

Data from high-latitude regions consistently point toward a survival advantage for patients undergoing surgery during the summer months.^7,9 In these territories, extreme fluctuations in the solar photoperiod mean that the “biological summer” provides the only window of sufficient ultraviolet B (UVB) exposure for adequate Vitamin D synthesis.^9,17 Some authors thought this oscillation in 25(OH)D levels during June and July may prime the immune system, enhancing the anti-tumor response at the critical moment of surgical tumor shedding.^2,19 Furthermore, in these cold climates, the summer season represents a period of minimal thermal stress, favoring homeostatic stability and reducing perioperative complication rates.^8,21

The Mediterranean perspective: Heat stress and autumnal advantage

On the contrary, other evidence from Mediterranean and southern regions suggests a different trend, reporting a survival peak in autumn or winter. ²² This discrepancy can be explained through the lens of environmental stress and chronodisruption. In southern countries, summer is often characterized by extreme heat, which can cause physiological stress.^22,24,26 As a result, high temperatures have been shown to disrupt the circadian rhythm of core body temperature, which serves as a fundamental coordinator of systemic rhythms.^4,5

As previously noted, the stability of these internal oscillators is a prerequisite for favorable host recovery.^5,26 In these contexts, the excessive thermal load of summer may act as a “pro-inflammatory” stimulus, counteracting the benefits of solar exposure and potentially leading to the relative immunodeficiency observed in experimental models during the warmer months.^15,17,27

The lag-phase and the “biological buffer”

To reconcile these findings, the “Lag-Phase” hypothesis suggests that the prognostic benefit of a season is not instantaneous but delayed. The cumulative effect of summer solar radiation on the immune system may reach its peak efficacy several weeks or months later. ⁹ This suggests that the high Vitamin D levels synthesized in summer could provide a protective “biological buffer” for patients treated in subsequent months.^19,25 Ultimately, the “optimal month” for NSCLC surgery is context-dependent, representing the point of intersection between maximum “positive drivers” (solar exposure, Vitamin D reserves) against minimum negative stressors (heat stress, healthcare delays).^22,27

The circadian timing of surgery: Morning vs. afternoon outcomes

The “time-of-day” effect in thoracic surgery is an emerging field of investigation. Retrospective analyses have suggested that the timing of pulmonary resection or radiotherapy can influence immediate post-operative outcomes and long-term survival.^28,29 Some authors postulated that patients undergoing elective surgery in the afternoon/night may experience a higher incidence of postop complication rates or mortality in specific cohorts.^29,30 Mechanistically, this has been linked to the circadian variation in pulmonary compliance and the rhythmic activity of alveolar macrophages, which exhibit a peak in phagocytic and inflammatory capacity during the early morning hours in humans.^2,31 Furthermore, anesthesia itself is a potent chronodisruptor; the interaction between volatile anesthetics and molecular clock genes (such as PER2) can either aggravate or mitigate ischemia-reperfusion injury during lung manipulation, depending on the circadian phase of the intervention.^32,33

Lessons from chronomodulated systemic therapy

The pioneering work in this field has established that the efficacy and toxicity of pharmacological agents are not constant but fluctuate according to the patient's internal clock. ³⁴ In lung cancer, chronomodulated chemotherapy—specifically the infusion of cisplatin or gemcitabine at specific circadian windows—has demonstrated a reduction in hematological toxicity by up to 30-40% compared to flat-rate infusions, while maintaining or even enhancing the objective response rate.^35,36 These findings have profound implications for the adjuvant setting in resectable NSCLC. If the “host soil” is more resilient at certain hours, the administration of adjuvant chemotherapy or immunotherapy (checkpoint inhibitors) should be synchronized with the acrophase of immune cell infiltration.^37,38 For instance, recent data on PD-L1 inhibitors suggest that infusions before 14:00 are associated with significantly better overall survival than late-afternoon infusions, a finding hypothesized to be related to circadian variation in T-cell activation.^37,38

Seasonal vaccination and immunological priming

In this context, an interesting and debated issue is the timing of seasonal influenza vaccination, especially considering that chronodisruption can significantly impair host immune surveillance. ³⁹ Beyond preventing respiratory infections, vaccination serves as an immunological “boost” that can modulate the host's systemic inflammation. Studies have shown that flu vaccination in cancer patients is not only safe but may provide an unintended survival benefit through a process of “trained immunity”.^40,41 In resectable patients, administering the vaccine in the weeks preceding surgery (during the autumn months) may prime the innate immune system, potentially reducing the risk of post-operative pneumonia and altering (or improving) the inflammatory response to surgical stress.^41,42

Critical analysis and current limitations

A significant bias for the adoption of specific chronobiological models stems from the heterogeneity of existing data. Specifically, most studies on seasonality in NSCLC analyzed retrospective registry data that often lack standardization for key confounding variables. ²² For instance, while Vitamin D levels are frequently cited as a primary driver of the “seasonal window,” few surgical cohorts include prospective, longitudinal measurements of 25(OH)D or VDR polymorphisms.^18,19,44

The molecular characterization of the “tumor clock” also faces challenges. Although the prognostic value of TIMELESS and RORA has been validated in large datasets, their clinical application is hindered by the lack of standardized immunohistochemical assays that can be performed on surgical specimens cost-effectively.^11,13,14,45 Moreover, the systemic impact of “humoral chronodisruption” means that the tumor’s clock cannot be viewed in isolation from the host's central oscillators.^15,43

The chrono-surgical protocol: A speculative framework

Despite these limitations, the synthesis of these data points toward the necessity of a “time-aware” oncological framework. A proactive surgical strategy for NSCLC should move beyond the static “waiting list” approach. As proposed by the emerging evidence, a future Chrono-Surgical Protocol would involve a multi-dimensional assessment ⁴⁶ :