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All issues Volume 6 (2025) Vis Cancer Med, 6 (2025) 8 Full HTML
Open Access
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Vis Cancer Med
Volume 6, 2025
Article Number 8
Number of page(s) 6
DOI https://doi.org/10.1051/vcm/2025008
Published online 11 June 2025

© The Authors, published by EDP Sciences, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Over the past few decades, chemotherapy has been the cornerstone of anti-tumor therapy for lung cancer, particularly for patients with advanced disease. By disrupting DNA, inhibiting cell division, and interfering with metabolic processes, chemotherapy effectively hinders the proliferation and survival of non-small cell lung cancer (NSCLC) cells, ultimately inducing tumor cell apoptosis [1]. The addition of anti-angiogenic agents and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies to chemotherapy regimens has further improved therapeutic efficacy. As the toxicity of chemotherapeutic agents has progressively decreased, numerous maintenance chemotherapy strategies have been shown to extend disease control and improve patient outcomes. For example, in the AVAPERL and ECOG-ACRIN 5508 trials [2, 3], long-term pemetrexed maintenance therapy significantly prolonged progression-free survival (PFS) in patients with lung adenocarcinoma. Similarly, the CECOG and IFCT-GFPC 0502 trials [4, 5] demonstrated that gemcitabine maintenance therapy not only provided substantial survival benefits for patients with squamous cell lung cancer but also enhanced their quality of life. In the era of chemotherapy, the sustained use of these agents remains a critical component in achieving the best possible treatment outcomes.

With the advent of small-molecule targeted therapies, patients with specific driver gene mutations, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene (ROS1), now have access to treatment options that are not only more precise but also more effective compared to traditional chemotherapy. For instance, in NSCLC with EGFR mutations, targeted therapies such as erlotinib, gefitinib, and osimertinib effectively halt tumor cell proliferation [6–8]. These drugs have demonstrated superior efficacy over conventional chemotherapy in numerous clinical trials. Targeted therapies significantly prolong patient survival while offering the advantage of reducing the toxic side effects commonly associated with chemotherapy. However, this does not imply that chemotherapy can be completely replaced. The combination of chemotherapy with targeted therapies has shown marked synergistic effects. This approach not only effectively delays the development of drug resistance but also significantly extends both PFS and overall survival (OS). In the JMIT study [9], for example, the combination of pemetrexed with gefitinib improved PFS compared to gefitinib alone (15.8 months vs. 10.9 months). Similarly, in the FLAURA2 study [10], combining third-generation tyrosine kinase inhibitors (TKI) osimertinib with chemotherapy increased PFS by approximately 9 months compared to osimertinib monotherapy, yielding significant survival benefits.

With the emergence of PD-1/PD-L1 pathway inhibitors, lung cancer treatment has rapidly entered the era of immunotherapy, expanding the therapeutic focus from the tumor cells themselves to the entire immune system. PD-1/PD-L1 immune checkpoint inhibitors work by blocking the inhibitory signals between T cells and tumor cells, thereby lifting the suppression of the immune system and restoring T cell activity [11]. This reactivation of T cells enhances the immune system’s ability to recognize and eliminate cancer cells. However, chemotherapy can have numerous negative effects on immune cells. It damages hematopoietic stem cells at the source, suppresses bone marrow function, and reduces the number and functionality of key immune cells such as T cells, B cells, and NK cells, weakening the overall immune response and directly impacting the effectiveness of immunotherapy [12, 13]. Chemotherapy may also impair antigen-presenting cells like dendritic cells and macrophages, reducing their ability to recognize and present antigens, which prevents effective T-cell activation [14, 15]. Additionally, chemotherapy-induced damage to the intestinal mucosa can lead to dysbiosis, or an imbalance in gut microbiota [16]. Given the critical role gut microbiota plays in regulating systemic immune responses, dysbiosis can weaken the microbiota’s potential to enhance the efficacy of immunotherapy [17]. In summary, chemotherapy may cause long-term damage to the immune system, leading to sustained depletion and dysfunction of immune cells, which may not fully recover even after chemotherapy has ended. This, in turn, can affect the long-term anti-tumor effects of immunotherapy. The conflicting mechanisms between chemotherapy and immunotherapy suggest that chemotherapy’s role will likely evolve in the era of immunotherapy, as it may limit the full potential of immune-based treatments.

However, based on previous studies, chemotherapy also offers several positive effects when combined with immunotherapy. For instance, chemotherapy can induce immunogenic cell death, increase antigen presentation, and eliminate immunosuppressive cells such as regulatory T cells (Tregs), thereby reshaping the immune microenvironment and enhancing the efficacy of immunotherapy [18]. Clinically, most chemo-immunotherapy combination regimens have proven successful. In particular, our team’s indirect comparison analysis revealed that even in patients with PD-L1 expression greater than 50%, the combination of chemotherapy and immunotherapy showed clear additional benefits over immunotherapy alone [19]. Moreover, chemotherapy can prevent hyperprogression in some patients, thereby avoiding accelerated disease worsening among those who do not respond to immunotherapy alone. Interestingly, we also found that chemotherapy can reduce common immune-related toxicities, such as those affecting the skin or thyroid [20]. This might be due to chemotherapy’s ability to prevent the overactivation of T cells, especially in normal tissues where antigen release is less continuous compared to within the tumor. That said, it is important to note that not all toxicities are reduced. For example, caution is needed regarding the potential for PD-1 inhibitors to exacerbate chemotherapy-induced bone marrow suppression, which may not be related to T cells.

Despite the transformative impact of targeted therapy and immunotherapy, chemotherapy remains indispensable for most patients. It should not be easily excluded, but rather, its use should be optimized. Here, we propose several strategies to optimize chemotherapy use:

Reduced chemotherapy duration and dosage

First, chemotherapy regimens can be adjusted, such as in the checkmate 9LA study and Hui Juan’s research [21, 22], where short-course chemotherapy acts as a “primer” to enhance the sensitization effect of chemotherapy. Short-course chemotherapy can quickly kill tumor cells in the early stages, induce immunogenic cell death, and release a large amount of antigens, thereby activating the immune system. At the same time, it avoids the long-term side effects of chemotherapy, such as bone marrow suppression, the accumulation of immunosuppressive cells, and increased toxic burden. By shortening the chemotherapy cycle, patients’ immune systems receive maximum “activation” early on, allowing immunotherapy to take over the primary anti-tumor response, thus reducing long-term chemotherapy-related toxicity. Compared to traditional continuous chemotherapy regimens, short-course chemotherapy enables patients to benefit from the sensitization effects of chemotherapy while reducing cumulative toxicity, significantly improving quality of life, and enhancing treatment tolerance. This strategy can also be flexibly adapted to different patient groups, especially for those with weaker constitutions or multiple comorbidities. Short-course chemotherapy provides a safer option, reducing the risk of treatment interruption and ultimately improving the effectiveness of immunotherapy.

The second approach is to reduce chemotherapy dosage, utilizing strategies such as oral administration, low-dose therapy, or metronomic chemotherapy to minimize toxicity and its impact on the immune system. For example, low-dose paclitaxel promotes dendritic cells’ ability to phagocytize tumor antigens and supports their maturation, which contrasts with high-dose paclitaxel, which induces dendritic cell apoptosis. Low-dose paclitaxel not only avoids inhibiting T cell proliferation but also maintains the balance of T cell subpopulations. In contrast, high-dose paclitaxel significantly reduces the proportion of CD8+ T cells without substantially affecting regulatory T cells [23]. In addition, in vitro models have shown that low-dose gemcitabine selectively eliminates Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs), thereby enhancing the activity of CD8+ T cells and NK cells, boosting anti-tumor immunity [24]. Metronomic chemotherapy has also been proven to effectively target heterogeneous tumor cell populations. More importantly, it can activate both innate and adaptive immune systems, transforming “cold” tumors (which are less responsive to immune therapies) into “hot” tumors that are more immunologically active. For instance, metronomic dosing of gemcitabine combined with a checkpoint kinase 1 (CHK1) inhibitor and anti-PD-L1/PD-1 immunotherapy significantly increased the presence of anti-tumor CD8+ cytotoxic T cells, dendritic cells, and M1 macrophages in small cell lung cancer (SCLC) models, while immunosuppressive M2 macrophages and MDSCs were significantly reduced [25]. Currently, several ongoing clinical trials are exploring the efficacy of metronomic chemotherapy combined with immunotherapy. In the VinMetAtezo trial, oral metronomic vinorelbine combined with atezolizumab demonstrated promising outcomes and safety in patients with NSCLC [26]. Similarly, in breast cancer patients, compared to traditional chemotherapy combined with PD-1 inhibitors, metronomic chemotherapy combined with PD-1 inhibitors was shown to reprogram the systemic immune response, resulting in significantly improved and sustained efficacy (median PFS: 3.5 vs. 6.6 months; median OS: 23.1 vs. 42.6 months) [27].

Third, targeted chemotherapies, such as antibody-drug conjugates (ADCs), may be considered to minimize reliance on platinum-based regimens. ADCs precisely recognize specific markers on tumor cell surfaces, like HER2 or Trop-2. Upon binding to these markers, the antibody component of the ADC delivers cytotoxic drugs directly to tumor cells, minimizing collateral damage to non-target cells and significantly reducing harm to the patient’s immune system. Preliminary findings from the EVOKE-02 study have shown promising anti-tumor efficacy of the ADC drug TRODELVY in combination with pembrolizumab as a first-line treatment for metastatic NSCLC, regardless of PD-L1 expression (overall response rate (ORR) of 56% and disease control rate (DCR) of 82%) [28]. Similarly, in the TROPION-Lung02 study, the ADC datopotamab deruxtecan (Dato-DXd), combined with pembrolizumab with or without platinum-based chemotherapy, demonstrated robust efficacy in NSCLC patients. The dual-therapy regimen achieved an ORR of 52% and a DCR of 88%, with an initial median PFS of 11.1 months. The triple regimen yielded an ORR of 56%, a DCR of 89%, and an initial median PFS of 6.8 months [29].

Another approach is on-demand chemotherapy, exemplified by our proposed “Chemo-Holiday” regimen [30]. This strategy involves an initial phase of combined immunotherapy and short-term chemotherapy to rapidly control tumor growth. During the maintenance phase, chemotherapy is paused, and treatment is sustained with immunotherapy combined with anti-angiogenic agents. When signs of disease progression appear, first-line chemotherapy is reintroduced as a “rechallenge.” In this process, we observed that approximately 50% of patients achieved partial response (PR) after the chemotherapy rechallenge. This suggests that an on-demand chemotherapy strategy can re-activate the therapeutic response upon tumor progression, allowing continued efficacy of immune checkpoint inhibitors (ICIs). By strategically timing chemotherapy, this approach reduces the toxic burden during maintenance, while also re-engaging therapeutic effects upon disease progression, extending the overall period of clinical benefit for patients.

Alternative strategies for chemotherapy: targeted therapies, anti-angiogenic agents, dual immunotherapy, and localized treatments

Another strategy is to replace chemotherapy with other options that inhibit tumor proliferation and reshape the tumor microenvironment, such as targeted therapies, anti-angiogenic drugs, dual immunotherapy, and localized treatments. In tumors with targetable driver gene mutations, targeted therapies can help control tumor progression, reduce tumor burden, and expose tumor antigens. For example, research on KRAS inhibitors combined with PD-1 inhibitors has shown promising results. In tumor-bearing mice treated with the KRAS inhibitor AMG510 and PD-1 blockade over 4 days, T cell and dendritic cell infiltration increased significantly, and IFN-γ-mediated antigen presentation on tumor cells was enhanced. The addition of KRAS inhibitors to ICIs counteracted PD-1 expression on T cells, induced T cell memory formation, and contributed to sustained anti-tumor effects [31]. Another study also verified the immune-modulatory role of KRAS G12C inhibitors, revealing that these inhibitors could shift macrophages from the M2 to M1 phenotype and significantly reduce the population of MDSCs [32]. Preliminary results from a recent RCT investigating the KRAS inhibitor Olomorasib in combination with pembrolizumab indicated encouraging outcomes [33]. Among treatment-naive KRAS patients, the ORR was 77% with a DCR of 88%. In pretreated patients, 81% had previously received immunotherapy, achieving an ORR of 40% and DCR of 81%. Regardless of PD-L1 expression levels, initial PFS results were favorable, and safety was manageable. While combining EGFR inhibitors with PD-1 therapy has been associated with significantly increased toxicity, such as a 5.09-fold higher risk of interstitial lung disease [34] and immune hepatitis toxicity as high as 38% [35], we believe this issue is specific to certain drugs rather than an inherent flaw in combination therapy. The observed toxicity increase is likely related to the characteristics of specific drugs rather than to insurmountable challenges with the combined treatment strategy itself.

Currently, the most common alternatives to chemotherapy often involve the combination of anti-angiogenic agents, particularly small-molecule VEGFR-TKIs. Anti-angiogenic drugs can reverse the immunosuppressive state of the tumor microenvironment and promote vascular normalization, which, when combined with PD-1 inhibitors, enhances anti-tumor efficacy through a synergistic effect. In a study of PD-1 antibody sintilimab combined with multi-target VEGFR-TKI anlotinib as a first-line treatment for NSCLC, the median ORR was 72.7%, PFS reached 15 months, and overall safety was favorable [36]. In the NCT03083041 study, the combination of camrelizumab and apatinib was evaluated for efficacy and safety in advanced non-squamous NSCLC patients who either failed first-line or later-line chemotherapy [37]. Even among PD-L1-negative patients, this combination provided sustained clinical benefits. Evidence from both first- and second-line studies indicates that these regimens offer a viable alternative for patients who are either ineligible or unwilling to undergo chemotherapy.

In addition, CTLA-4 inhibitors can be considered as sensitizers in immunotherapy combinations. CTLA-4 inhibitors enhance the immune system’s recognition and attack on tumor cells by modulating early T cell activation, thereby improving anti-tumor efficacy. For example, in the CheckMate 227 study [38], the combination of ipilimumab with nivolumab proved more effective than PD-1 inhibition alone, particularly in patients with low or even negative PD-L1 expression. This dual ICI combination outperformed not only single-agent PD-1 inhibition but, in certain aspects, also surpassed traditional chemotherapy-based regimens. The study results suggest that CTLA-4 inhibitors can serve as potent sensitizers by boosting the immune response, providing improved outcomes for patients with low PD-L1 expression, a challenging group to treat in clinical practice. In our own clinical experience, we reported a case of a patient with MET exon 14 skipping mutation squamous lung cancer who had developed resistance to both immunochemotherapy and MET-targeted therapy. Remarkably, this patient achieved a complete response (CR) with a dual immunotherapy regimen combining PD-1 and CTLA-4 inhibitors. This highlights the potential of CTLA-4 inhibitors to offer an innovative and effective strategy for patients with difficult-to-treat cancers [39].

Local treatments offer an effective alternative to reduce the systemic effects of chemotherapy, including options like stereotactic body radiation therapy (SBRT), ablation, and tumor-treating fields. These approaches not only effectively directly eliminate tumor cells but also show significant synergy with immunotherapy, particularly when combined with PD-1 inhibitors. For example, SBRT, a high-precision, high-dose radiotherapy technique, targets tumor cells accurately within a short period while minimizing damage to surrounding healthy tissue. The PEMBRO-RT study was the first to investigate the efficacy of pembrolizumab maintenance after SBRT in advanced lung cancer, finding that the combination doubled the 12-week ORR compared to the control group (36% vs. 18%), with the greatest radiotherapy benefit observed in PD-L1-negative tumors [40]. Similarly, the LUN 14-179 study showed that advanced NSCLC patients receiving consolidation pembrolizumab after concurrent chemoradiotherapy achieved a median PFS of 18.7 months and OS of 35.8 months [41]. The PACIFIC trial, which included 713 patients with unresectable, locally advanced NSCLC, demonstrated that consolidation therapy with durvalumab after concurrent chemoradiotherapy significantly improved time to metastatic disease or death (TMDD) and median PFS (23.2 and 16.8 months, respectively), with a marked improvement in OS compared to the placebo group (not reached vs. 28.7 months) and manageable toxicity [42]. Additionally, cryoablation has been shown to trigger a type I interferon-dependent anti-tumor immune response, increasing CD8+ T cell infiltration and enhancing features such as interferon response and cytolytic activity. When combined with PD-1 inhibitors, this approach has demonstrated a potent synergistic effect in NSCLC patients [43].

Optimizing chemotherapy deployment: the chemo-holiday strategy

To optimize the integration of chemotherapy with immunotherapy, it is crucial to effectively control disease while minimizing the systemic toxicities associated with chemotherapy and avoiding its long-term immunosuppressive effects, which can limit the efficacy of immunotherapy. Our team has developed and refined the “Chemo-Holiday” approach in previous studies, advocating for a flexible, targeted use of chemotherapy within immunotherapy regimens. This innovative treatment strategy allows for a more precise application of chemotherapy, enhancing treatment effectiveness while reducing adverse impacts.

The Chemo-Holiday approach combines short-term chemotherapy, anti-angiogenic agents, and immunotherapy, aiming to enhance the efficacy of immunotherapy while avoiding the long-term immunosuppressive effects of traditional chemotherapy. This strategy unfolds in three main phases: (a) Initial Induction Phase: Short-course immunotherapy is combined with chemotherapy and an anti-angiogenic agent (typically for 2–4 cycles) to control tumor growth, release antigens, and enhance the immune system’s ability to recognize and target tumor cells. (b) Chemo-Free Phase: Chemotherapy is halted, and maintenance therapy continues with ICIs and anti-angiogenic agents, thereby reducing cumulative toxicity. (c) Rechallenge Phase: If disease progression occurs, first-line chemotherapy is selectively reintroduced based on the patient’s specific needs. Remarkably, after reapplying the initial chemotherapy in progressing patients, approximately 50% achieved PR. This flexible, phased strategy not only minimizes toxicity and enhances immune response but also achieves PFS comparable to that of long-term ICI chemotherapy, which provides a more sustainable therapeutic option for patients.

One of the core advantages of the Chemo-Holiday strategy is its ability to enhance immune sensitivity. The use of short-term chemotherapy stimulates the immune system to increase its sensitivity to tumors, avoiding the immunosuppressive effects of prolonged chemotherapy and preventing the risk of hyper-progression that may occur with ineffective single-agent immunotherapy. Additionally, minimizing immunosuppression associated with long-term chemotherapy is another key feature of this approach. By reducing the chemotherapy duration, this model effectively allows immune cells to recover maximally during treatment breaks, enabling the immune system to continue targeting tumor cells. The Chemo-Holiday strategy also offers practical benefits by reducing toxicity and costs. Unlike traditional long-term chemotherapy regimens, this approach reduces chemotherapy use without compromising efficacy, significantly lowering related toxicity and financial burden. Fewer chemotherapy cycles also improve patient quality of life by reducing the side effects experienced during treatment. Furthermore, the Chemo-Holiday model assists in identifying patients genuinely responsive to immunotherapy. Chemotherapy’s side effects can sometimes obscure the actual effectiveness of immunotherapy. By employing this phased approach, clinicians can more clearly observe a patient’s true response to immunotherapy, allowing for a more tailored and effective subsequent treatment strategy.

In conclusion, with the continuous emergence of highly effective drugs with diverse mechanisms, cancer treatment is undergoing a profound transformation. These advancements enable us to reimagine and optimize the role of chemotherapy, moving beyond its use as the sole treatment backbone and integrating it with innovative therapies like immunotherapy and targeted therapy. The Chemo-Holiday approach exemplifies this shift, combining short-term immunotherapy, chemotherapy, and anti-angiogenic agents initially, followed by maintenance with immunotherapy and anti-angiogenics, and then on-demand chemotherapy rechallenge. By finding a balance between chemotherapy and immunotherapy, this approach reduces chemotherapy-related side effects while maintaining the long-term efficacy of immunotherapy.

Transitioning from the traditional “Chemo-on” model of continuous chemotherapy, we are steadily entering a “Chemo-less” era, where chemotherapy frequency and dosage are minimized, and immunotherapy along with anti-angiogenic treatments compensate for the potential efficacy gap. This trend makes chemotherapy no longer the only treatment option, allowing patients to receive more personalized and precise treatments at different therapy stages. With further clinical trials and data accumulation, a completely “Chemo-free” model may soon shift from concept to clinical reality. Through innovative drugs and combination therapies, chemotherapy’s role is evolving from a long-term mainstay to a short-term activator and regulatory support. Within this framework, patients can experience longer survival and enhanced quality of life, with fewer chemotherapy-related toxicities.

Thus, with these new treatment options and strategies, cancer therapy is advancing toward greater precision, personalization, and reduced toxicity, signaling the arrival of a new era in cancer care. As research progresses, we anticipate the development of even more innovative solutions to further enhance treatment outcomes and quality of life for cancer patients.

Funding

The National Natural Science Foundation of China (Grant No. 82022048, 81871893).

Conflicts of interest

No potential conflicts of interest were disclosed.

Data availability statement

All data generated or analyzed during this study are included in this published article and its references. No additional datasets were generated or analyzed for this study.

Author contribution statement

Feng Li, Boao Jiang, and Xianze Fan contributed to literature review, drafting, and conceptual framework design. Ziyan Jiang assisted in reference management and manuscript formatting. Jianxing He and Wenhua Liang supervised the project, provided critical revisions, and approved the final manuscript. All authors read and approved the final version of the manuscript.

Ethics approval

This study is a narrative review based on previously published research and does not involve human participants or animal experiments; thus, ethical approval was not required.

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Cite this article as: Li F, Jiang B, Fan X, Jiang Z, He J & Liang W. The next steps for chemo-optimization in lung cancer treatment. Visualized Cancer Medicine. 2025, 6, 8. https://doi.org/10.1051/vcm/2025008.

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