Search Results (4,713)

Background/Objectives: Renal cell carcinoma (RCC) care has been reshaped by immune checkpoint inhibitors (ICIs), now used across adjuvant and metastatic settings as PD-1/PD-L1 blockade alone, combined with anti-CTLA-4 agents, or in combination with vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitors (TKIs). As survival improves and systemic therapy courses extend, survivorship priorities—including fertility preservation, reproductive endocrine health, contraception, and pregnancy counselling—become increasingly relevant, even though RCC-specific oncofertility evidence remains sparse. This review examines the biological rationale and clinical considerations underpinning reproductive counselling for women of reproductive age exposed to ICIs (alone or with TKIs) in RCC. Methods: A narrative review was conducted in accordance with the SANRA framework, integrating targeted PubMed/MEDLINE searches up to 20 February 2026 and consultation of regulatory product labels to synthesize mechanistic, clinical, and safety data relevant to fertility, endocrine function, contraception, pregnancy, and breastfeeding in RCC. Results: We delineate the contemporary RCC treatment landscape to identify feasible timepoints for fertility preservation discussions and propose a pragmatic, implementation-oriented counselling framework that distinguishes evidence-secure recommendations (pregnancy avoidance during therapy, endocrine monitoring, agent-specific washout) from extrapolative domains (long-term ovarian reserve effects and post-ICI periconception safety beyond label intervals). Conclusions: By integrating a ‘multi-hit’ biological rationale, treatment context, and available human data, this review highlights RCC-specific research priorities while supporting transparent, evidence-aligned, and multidisciplinary counselling for both fertility preservation and pregnancy safety in the ICI era. Full article

Background: Orthodontic tooth movement is traditionally explained through mechanical deformation of the periodontal ligament (PDL); however, increasing evidence indicates that immune mechanisms critically shape bone remodeling outcomes. Mechanical stimuli influence immune cell recruitment, cytokine release, and phenotypic polarization, but these components are rarely integrated into a unified framework. Conceptual framework: We propose the Osteoimmune Axis Model, a conceptual framework describing how mechanical loading may bias immune polarity and thereby gate periodontal remodeling. Compressive loading appears to favor an M1 macrophage/Th17-dominant program associated with pro-inflammatory cytokines and enhanced RANKL-mediated osteoclastogenesis. In contrast, tensile or physiological strains may favor M2 macrophages and regulatory T cells (Treg), supporting IL-10, TGF-β, angiogenesis, extracellular-matrix repair, and osteoblastic activity. Stromal cells are proposed to act as mechanosensors and immune amplifiers that shape cytokine gradients and feedback loops. Predictions: The model predicts that identical forces may produce divergent outcomes depending on immune baseline; load duration may be more destructive than peak magnitude; tensile strain may stabilize M2/Treg pathways; thin periodontal phenotypes may shift toward the catabolic pole at lower mechanical loads; ROS may amplify immune-mediated bone loss; and immunomodulation may raise the threshold for pathological remodeling. Conclusion: The Osteoimmune Axis integrates mechanobiology and immunology into a testable framework for explaining variability in orthodontic periodontal remodeling and for generating hypothesis-driven, immune-aware risk assessment. Full article

Dendritic cells (DCs) are key sentinels in the lung mucosa that interpret environmental signals to either promote tolerance or trigger inflammation, influencing the development of chronic lung diseases. This review highlights recent mechanistic insights showing that metabolic checkpoints serve as upstream regulators of DC fate and activity: inflammatory stimuli activate HIF-1α/mTOR-linked glycolytic pathways that drive maturation, cytokine secretion, antigen presentation, and migration. In contrast, AMPK-related oxidative and lipid metabolism pathways support tolerogenic states that encourage regulatory T-cell responses and inhibit checkpoints like PD-1/PD-L1. We also present evidence that DC subset specialization (cDC1 vs. cDC2) and their tissue location interact with these metabolic pathways to regulate lymphoid tissue formation, including the development and persistence of tertiary lymphoid structures in chronically inflamed lungs. These ectopic lymphoid tissues enhance local immune responses through DC–stromal interactions and ongoing T follicular helper–B cell communication, contributing to persistent inflammation and tissue remodeling in conditions such as COPD, asthma, pulmonary hypertension, and fibrotic interstitial lung disease. Finally, we discuss the translational potential of targeting this immunometabolic–lymphoid pathway, suggesting that modulating metabolic regulators, migratory circuits, and tolerogenic programs could restore immune balance while maintaining host defense—a promising framework for developing advanced therapies for chronic lung inflammation. Full article

Background and Objectives: A combination of chemotherapy and immunotherapy may improve cancer treatment outcomes; however, determining which patient groups will benefit from immunotherapy is critical. Triple-negative breast cancer (TNBC) achieves limited benefit from immune checkpoint inhibitors (ICIs) and anti-PD-L1 blockade therapy. Materials and Methods: In this study, PD-L1 expression levels in myeloid-derived cells in the tumor microenvironment were determined in an experimental TNBC model. Results: Compared with tumor cells, granulocytes, monocytes, and macrophages had significantly higher PD-L1 expression. CD206⁺ tumor-associated macrophages (TAMs) expressed the highest level of PD-L1. PD-L1 positivity in TAMs was also significantly high in the lung, liver, lymph node, and spleen. Despite treatment initiation in late-stage tumorigenesis, the combination of paclitaxel and the anti-PD-L1 monoclonal antibody atezolizumab significantly reduced tumor growth. In addition, lung metastasis burden was reduced with combined treatment compared with chemotherapy or anti-PD-L1 monotherapy alone. Conclusions: As a result, alterations in PD-L1⁺ myeloid cells and immune infiltration can be associated with atezolizumab and paclitaxel therapy success in triple-negative breast cancer. Full article

Background: Immune checkpoint inhibitors (ICIs) have become the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression. However, the optimal selection between immunotherapy monotherapy and chemo-immunotherapy in patients with a PD-L1 tumor proportion score (TPS) ≥ 50% remains uncertain in routine clinical practice. Methods: We retrospectively reviewed patients with metastatic NSCLC and a PD-L1 TPS ≥ 50% who initiated first-line treatment with pembrolizumab monotherapy or pembrolizumab combined with platinum-based chemotherapy at the Istanbul Medipol University Department of Medical Oncology between July 2017 and December 2024. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated and compared according to PD-L1 expression levels and treatment strategy. Prognostic factors associated with survival outcomes were also explored. Results: A total of 65 patients were included, of whom 36 received pembrolizumab plus chemotherapy and 29 received pembrolizumab monotherapy. The estimated median PFS and OS for the entire cohort were 24.2 months (95% CI, 6.5–33.0) and 34.6 months (95% CI, 6.5–62.7), respectively. Patients with very high PD-L1 expression (TPS ≥ 90%) experienced significantly longer survival outcomes compared with those with a TPS of 50–89%, and a PD-L1 TPS ≥ 90% remained an independent prognostic factor for OS. When treatment strategies were compared across the entire cohort, no statistically significant differences in PFS or OS were observed between immunotherapy monotherapy and chemo-immunotherapy. Hypertension was identified as an independent negative prognostic factor for PFS. In patients with a PD-L1 TPS ≥ 90%, survival outcomes numerically favored pembrolizumab monotherapy, although this difference did not reach statistical significance. Conclusions: In this real-world cohort of patients with PD-L1 high metastatic NSCLC, PD-L1 expression, particularly very high TPS levels, was strongly associated with survival outcomes. While no survival differences were observed between treatment strategies in the overall population, pembrolizumab monotherapy may represent an appropriate first-line option in selected patients with a PD-L1 TPS ≥ 90%. Larger prospective studies are warranted to refine treatment selection in this setting. Full article

Background/Objectives: Patients with metastatic breast cancer and visceral crisis are systematically excluded from clinical trials, leaving clinicians without evidence-based therapeutic guidance. To the best of our knowledge, no published reports have described the use of combined chemo-immunotherapy in mTNBC complicated by hepatic visceral crisis. Case presentation: We report the case of a 45-year-old woman with PD-L1-high recurrent TNBC who presented with acute, life-threatening hepatic failure. Laboratory evaluation revealed marked transaminase elevation, cholestasis, rising bilirubin levels, and clinical deterioration consistent with hepatic visceral crisis. Due to severe hepatic impairment, a sequential therapeutic strategy was adopted: treatment was initiated with dose-reduced weekly paclitaxel (80% of the standard dose), and pembrolizumab (200 mg every three weeks) was introduced at the fourth cycle. Shortly after immunotherapy initiation, the patient experienced rapid clinical improvement accompanied by significant biochemical recovery and radiologic tumor regression. Although disease progression occurred after four months, hepatic visceral crisis did not recur. Discussion: This case questions the conventional restriction of immunotherapy in the setting of severe hepatic dysfunction. The rapid biochemical recovery observed after pembrolizumab initiation suggests that immunologic antitumor activity may be preserved despite significant hepatic impairment. Furthermore, the high PD-L1 expression in this patient indicates that its predictive value may extend even to the context of visceral crisis. Conclusions: Our findings suggest that immunotherapy in combination with chemotherapy may represent a feasible therapeutic strategy in selected patients with PD-L1-high mTNBC presenting with hepatic visceral crisis. Full article

Neuroinflammation is pivotal in the development of numerous neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Microglial cells, the principal immune cells of the central nervous system (CNS), are essential mediators of this process. Upon exposure to pathogenic stimuli such as lipopolysaccharide (LPS), microglia activate and release pro-inflammatory mediators, leading to heightened oxidative stress and neuronal damage. Therefore, targeting microglial activation is a promising therapeutic approach to prevent or slow neurodegeneration. This study aimed to investigate the antioxidant and anti-inflammatory effects of the leaf extract of the newly identified species Bauhinia thailandica on LPS-activated BV2 microglia. The phytochemical compound of the B. thailandica leaf extract was also investigated. BV2 cells were treated with LPS (1 μg/mL) for 24 h in the presence or absence of B. thailandica leaf extract (12.5 and 25 µg/mL). The levels of reactive oxygen species (ROS), nitric oxide (NO), and interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α) were quantified with CM-H2DCFDA, Griess reagent assay, and ELISA, respectively. Treatment with LPS resulted in significant increases in ROS, NO, IL-6, IL-1, and TNF levels compared to untreated cells (p < 0.01). However, co-treatment with B. thailandica leaf extract significantly suppressed the production of these inflammatory markers (p < 0.01 for 25 µg/mL across all parameters, except TNF-α; p < 0.05). The results also showed that B. thailandica leaf extract possessed significant levels of total phenolic content (TPC; 70.55 mg GAE/g dry extract), total flavonoid content (TFC; 249.47 mg QE/g dry extract), and tannins (397.50 mg TAE/g dry extract). Phytochemical screening also revealed the presence of saponins and cardiac glycosides in the extract. In conclusion, the leaf extract of B. thailandica is a potent source of phytochemicals exhibiting antioxidant capabilities and has shown both antioxidant and anti-inflammatory actions in LPS-activated BV2 microglial cells. The findings indicate that B. thailandica leaf extract shows significant promise as a novel herbal treatment for neuroinflammatory disorders mediated by microglia. Further research is necessary to clarify the underlying mechanisms of action and to investigate the active substances responsible for these effects. Full article

Background/Objectives: Programmed death ligand 1 (PD-L1) is often overexpressed in triple-negative breast cancer (TNBC), where it helps the tumor evade the immune system and promotes tumor growth. Interleukin-24 (IL-24) is recognized for its anti-tumor activity, although its role in immune regulation remains unclear. In this study, we examined the role of IL-24 in regulating PD-L1 and its anti-cancer activity in TNBC cells. Methods: The study used TNBC cell lines treated with IL-24, delivered via a non-replicating adenovirus vector expressing the IL-24 gene. Assays included MTT for cell viability, Annexin V for apoptosis, Western blot for protein analysis, and qRT-PCR for mRNA analysis. Results: We found that the highly aggressive MDA-MB-231 cells had significantly higher PD-L1 levels. We discovered that treatment with IL-24 reduced cell growth, induced apoptosis, and significantly decreased PD-L1 protein levels in MDA-MB-231 cells. Mechanistically, we identified PKR, also known as eukaryotic translation initiation factor 2 alpha kinase 2, as a key mediator of IL-24–induced PD-L1 suppression. Additionally, doxorubicin, a primary chemotherapy drug used to treat triple-negative breast cancer, decreases PD-L1 expression and increases the sensitivity when combined with IL-24. Conclusions: In this study, we show that IL-24 decreases PD-L1 expression in MDA-MB-231 cells through PKR activation, enhances the anti-tumor effects of Doxorubicin, and may enable lower doses that reduce toxicity and further decrease PD-L1 levels. These findings suggest that IL-24 could serve as a valuable target for therapeutic intervention and suggest that it can improve doxorubicin’s effectiveness against aggressive breast cancer. Full article

Background/Objectives: The aztreonam/avibactam combination represents a promising therapeutic option for severe infections caused by multidrug-resistant Gram-negative pathogens, particularly in critically ill patients. Due to marked pharmacokinetic variability and the need to achieve joint pharmacokinetic/pharmacodynamic (PK/PD) targets of both agents, therapeutic drug monitoring (TDM) may play a pivotal role in optimizing treatment. This study aimed to develop and validate two rapid, accurate, and sensitive UHPLC–qTOF MS/MS sequential methods for quantifying aztreonam and avibactam in human plasma, suitable for routine clinical TDM. Methods: Plasma concentrations were determined by means of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC–qTOF MS/MS), operating in positive and negative electrospray ionization modes for aztreonam and avibactam, respectively. Sample preparation consisted of protein precipitation with isotopically labeled internal standards. The method’s validation was performed according to the European Medicines Agency guidelines, by assessing selectivity, linearity, precision, accuracy, recovery, matrix effects, carry-over, and stability. Clinical applicability was evaluated by reprocessing plasma samples, which were already previously collected for routine clinical practice from 20 hospitalized patients undergoing treatment with ceftazidime-avibactam plus aztreonam. Results: The methods showed excellent linearity (R² ≥ 0.999) over ranges of 0.2–100 µg/mL for aztreonam and 0.1–50 µg/mL for avibactam. Lower limits of quantification were 0.2 µg/mL and 0.1 µg/mL, respectively. Intra- and inter-day precision and accuracy met the EMA criteria at all of the quality control levels. Extraction recovery exceeded 90% for both analytes, and matrix effects were effectively compensated by internal standards. Stability testing highlighted the need for careful sample handling, particularly for aztreonam under repeated freeze–thaw conditions. Clinical application revealed substantial inter-individual variability in steady-state concentrations. Conclusions: The validated UHPLC–qTOF MS/MS assays provide robust and sensitive sequential quantification of aztreonam and avibactam in human plasma, supporting TDM-guided dose optimization in clinical practice. Full article

Nanotechnology combined with photodynamic therapy (PDT) has been explored to enhance antitumor and antimicrobial photobiological activity. Aluminum phthalocyanine chloride (Al-Pc-Cl), with or without magnetic nanoparticles (MagNPs), was incorporated into polymeric nanoparticles (PNPs) to improve the PDT for treating tumors and infectious diseases. Three batches of the nanoparticles (MagNPs, PNPs-PS and PNPs-PS-MagNPs) were developed and characterized in terms of size, PdI, morphology by TEM, release study, and antitumor (against A549 cells) and antimicrobial (against MRSA and C. albicans) photobiological activity. The developed nanoparticles were nanometric in size, with MagNPs, PNPs-PS, and PNPs-PS-MagNPs showing 33.6, 186.9, and 333.5 nm, respectively, maintained the magnetic properties (for MagNPs and PNPs-PS-MagNPs), and provided slow and sustained release of the photosensitizer. PNPs-PS and PNPs-PS-MagNPs showed excellent antitumor photobiological activity with cell viabilities of 42 and 34%, respectively, and were not cytotoxic in the dark, with cell viabilities above 70%. PNPs-PS showed strong antibacterial activity against MRSA with an IC₅₀ of 8.26 μg/mL, which was lower to free Al-Pc-Cl with an IC₅₀ of 14.22 μg/mL after I radiation. The results of the antifungal photobiological activity against C. albicans were excellent, with IC₅₀ values of 3.75 and 3.5 μg/mL for PNPs-PS and PNPs-PS-MagNPs, respectively, values which were significantly lower with p < 0.05 than free PS (IC₅₀ > 30 μg/mL) after irradiation with light and fluconazole (IC₅₀ > 30 μg/mL), the reference antifungal agent. PNPs-PS showed promising results regarding antitumor, antibacterial, and antifungal photobiological activity. However, PNPs-PS-MagNPs showed weak results for antibacterial photobiological activity against MRSA but with promising results for tumor cells and C. albicans. Full article

Background: First-line chemoimmunotherapy (I + C) is the standard of care for advanced non-squamous non-small cell lung cancer (NSCLC) without oncogenic mutation. Bevacizumab has been shown to enhance the efficacy of chemotherapy in non-squamous NSCLC, yet its added value when combined with I + C (I + C + B) remains unclear. To address this gap, we conducted a real-world comparative study and a network meta-analysis to evaluate I + C + B versus I + C in this setting. Methods: This retrospective study included patients with advanced EGFR/ALK-negative non-squamous NSCLC treated with first-line I + C + B or I + C. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Efficacy endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined outcomes by PD-L1 expression, age, metastases, and chemotherapy, among other factors. In parallel, a network meta-analysis of four randomized trials (n = 2026) indirectly compared I + C + B against I + C for PFS, OS, and safety outcomes. Results: A total of 277 patients were included, with 167 (60.3%) receiving I + C + B and 110 (39.7%) receiving I + C. Before PSM, the I + C + B regimen significantly prolonged PFS versus I + C (hazard ratio [HR] = 0.69, 95% CI 0.52–0.92, p = 0.010), with this benefit maintaining post-matching (HR = 0.70, 95% CI 0.49–0.99, p = 0.045). However, OS did not differ significantly between groups in either the pre-PSM (HR = 0.93, 95% CI: 0.67–1.30; p = 0.665) or matched analyses (HR = 0.84, 95% CI: 0.54–1.29; p = 0.421). Subgroup analyses suggested greater PFS benefit from I + C + B among PD-L1-negative, older patients, those with brain metastases or multiple metastatic sites, and in patients receiving specific chemotherapy doublets. The network meta-analysis confirmed a PFS advantage for I + C + B over I + C (HR = 0.84, 95% CI: 0.71–0.98) without an OS benefit (HR = 0.95, 95% CI: 0.79–1.14). Toxicity was higher with I + C + B; rates of grade 3–5 adverse events, serious adverse events, and treatment discontinuation were all significantly increased compared to I + C. Conclusions: In the first-line treatment of advanced EGFR/ALK-negative non-squamous NSCLC, adding bevacizumab to I + C improved PFS but did not translate into an OS gain. Although PFS benefits were observed in certain subgroups, these were accompanied by significantly increased treatment-related toxicities. Our findings suggest that no clear subgroup has been identified where the benefit outweighs the risks, necessitating extreme clinical caution. Full article

Background/Objectives: Protein–protein interactions (PPIs) involving oncogenic drivers remain among the most intractable targets in cancer biology due to their dynamic conformations and limited accessibility to conventional small molecules. Although antibodies and inhibitors have achieved clinical success against targets such as PD-1/PD-L1 and MYC, challenges persist related to tissue penetration, intracellular delivery, resistance, and incomplete blockade of key interface hotspots. The objective of this study is to develop an integrated computational framework for systematically designing hotspot-conditioned de novo miniprotein binders to target these interfaces. Methods: We present DesignForge, a computational protein design pipeline that integrates energetic hotspot identification, generative backbone design, sequence optimization, and structural confidence evaluation. The framework combines hotspot mapping using an open force-field-based energetic analysis module with generative backbone sampling using BindCraft, sequence optimization using ProteinMPNN, and structural validation using AlphaFold2. This in silico pipeline was applied to three representative oncogenic interfaces: PD-1/PD-L1, MYC/MAX, and KRAS/RAF. Results: Computationally generated designs exhibited high predicted structural confidence, favorable interface energetics, and consistent engagement of identified hotspot residues across targets. AlphaFold2-Multimer structural modeling indicated that the candidate PD-1 mimetic scaffolds, MYC/MAX interface binders, and KRAS interaction candidates can adopt conformations compatible with the target interfaces. Energetic contact analysis further supported predicted engagement of key hotspot residues. These findings support the computational feasibility of hotspot-conditioned binder generation using a unified design workflow. Conclusions: DesignForge provides a reproducible computational framework for hotspot-guided de novo protein binder design targeting oncogenic protein–protein interfaces. The designs reported here represent computational predictions derived from structural modeling and energetic analysis. Experimental biochemical and cellular validation will be required to determine the functional activity of the proposed binders. Full article

Programmed Death-Ligand 1 (PD-L1) promotes tumor progression through several mechanisms, including its intrinsic effect on breast cancer cell proliferation via the S-Phase Kinase-Associated Protein 2 (SKP2)–p21^Cip1/p27^Kip1 (SKP2-p21/p27) axis. However, the specific regulatory signaling through which PD-L1 influences the SKP2–p21/p27 axis to drive cell proliferation remains unclear. To investigate how PD-L1 mediates SKP2-dependent proliferation, proteomic analyses, gene-expression manipulation via knockdown or overexpression, Western blotting, quantitative immunofluorescence, colony-forming assays, real-time cell analysis, and Xenograft-derived cells were used. Proteomic data analysis identified several PD-L1 downstream targets as potential candidate regulators of the SKP2–p21/p27 axis and activators of the PI3K/AKT pathway. Candidate screening by gene knockdown, followed by analyses of SKP2, p21, and p27 protein expression, revealed Livin and Galectin-1 as upstream regulators of the SKP2–p21/p27 axis. Moreover, Western blotting and quantitative immunofluorescence in three breast cancer cell lines confirmed that PD-L1 is an upstream regulator of Livin, Galectin-1, and SKP2 protein expression. Mechanistically, Livin and Galectin-1 enhanced AKT phosphorylation (Ser473) to sustain PI3K/AKT pathway activation in a positive feedback loop to upregulate SKP2 expression. Functional assays, including colony-forming assays and real-time cell analyzer, demonstrated that Livin and Galectin-1 are critical for PD-L1-mediated, SKP2-dependent proliferation. These findings were corroborated in vivo using xenograft-derived cells. Overall, these findings delineate a tumor-intrinsic signaling axis in which PD-L1 upregulates Livin and Galectin-1 to sustain PI3K/AKT activity and drive SKP2-dependent cell proliferation. Targeting Livin and/or Galectin-1 may provide a rational strategy to disrupt PD-L1-associated proliferative signaling and improve combinatorial therapeutic approaches in breast cancer. Full article

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC₅₀ values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC. Full article

Immunotherapy, particularly effective in tumors with a high mutational burden, is very often administered in combination with chemotherapy. Several tumor types with a high mutational rate include melanoma and non-small cell lung cancer (NSCLC), which are particularly sensitive to immunotherapy. For NSCLC, conventional platinum-based doublet chemotherapy has been extended with drugs targeting signaling pathways (such as the epidermal growth factor receptor) and immune checkpoint inhibitors (ICI) directed against PD-1 and PD-L1. This review highlights the potential role of the membrane antigens CD73 and CD39 in enhancing the efficacy of combined immuno-chemotherapy. These ecto-nucleotidases catalyze the degradation of extracellular ATP to AMP and subsequently to adenosine (Ado), a potent immunosuppressive metabolite that acts through adenosine receptors. Consequently, CD73 and CD39 function as key downregulators of immunogenic signaling. Both CD73 and CD39 are highly expressed not only on tumor cells but also on immune and endothelial cells within the tumor microenvironment. Conventional chemotherapy may further upregulate their expression, contributing to drug resistance and impaired immune responses. To counteract these effects, inhibitors of CD73 and CD39, both monoclonal antibodies and small molecules, are currently under clinical evaluation, with early results indicating potential therapeutic benefit. Although this evidence supports the involvement of CD73 and CD39 in modulating responses to immunotherapy, particularly in combination with chemotherapy, the precise mechanisms underlying these interactions remain unclear. Elucidating these pathways will be critical for optimizing treatment strategies and improving clinical outcomes in malignancies such as NSCLC. This review highlights the critical role of these pathways in optimizing treatment strategies and improving clinical outcomes in malignancies such as NSCLC. Full article