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Antibiotics and probiotics differentially shape immunotherapy outcomes in non-small cell lung cancer

Shuling Ma, Zijun Zhai, Rui Ding, Shijie Shang, Xinyi Liang, Shan Yin, Haofeng Lin, Guomeng Sha, Ran Zhang, Jinming Yu, Qian Song and Dawei Chen
Cancer Biology & Medicine May 2026, 20250844; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0844

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  • Table 1

    Detail characteristics of 34 antibiotic (ATB) cohort included in the meta-analysis

    AuthorYearCountryTrial typeMedian follow-upCancer typeNLine of therapyAntibiotics regimen in relation to ICITime frameImmunotherapyAntibioticReferences
    Derosa et al.2018FranceRetrospective cohort-Advanced NSCLC239Mixed line≤30 days before ICI initiation; also ≤60 days explored-Anti-PD-(L)1 alone or anti-PD-(L)1 + anti-CTLA-4β-lactams most common; also quinolones and sulfonamides3
    Huemer et al.2018AustriaRetrospective single-center study-NSCLC30All were 2nd-line or above1 month before ICI to 1 month after ICI2015.5–2017.11Nivolumab (25), pembrolizumab (5)Penicillins (64%), fluoroquinolones (36%), carbapenems (18%)4
    Zhao et al.2019ChinaSingle-center retrospective study-Advanced NSCLC109Mixed lines; first line 28 (25.7%), ≥ second line 81 (74.3%)Within 1 month before or after first ICI2016.1–2018.5Pembrolizumab, nivolumab, SHR-1210 (camrelizumab)Most commonly β-lactam inhibitors and fluoroquinolones5
    Barrón et al.2019Multiple Latin American countries (Mexico, Colombia, Argentina, Peru, and Brazil)Multicenter retrospective study-Advanced NSCLC140Mostly ≥2nd lineWithin 30 days prior to ICI initiation-PD-1/PD-L1β-lactams, quinolones6
    Bagley et al.2019USARetrospective cohort study using Flatiron Health EHR-derived database-Advanced NSCLC1,960First-linePrimary analysis: ABX from −6 to +4 weeks around ICI start; secondary analyses: within 6 weeks pre-ICI and within 4 weeks post-ICI-ICI-7
    Hakozaki et al.2019JapanRetrospective single-center study-Advanced NSCLC90Second or later lineAntibiotics for ≥3 days within 30 days of nivolumab therapy2016.1–2017.4Nivolumab monotherapyTMP/SMX, amoxicillin/clavulanate, ceftriaxone, meropenem, piperacillin/tazobactam, ampicillin/sulbactam, cefazolin, levofloxacin8
    Kim et al.2019KoreaRetrospective single-center study-Advanced NSCLC131Mixed-lineAntibiotics within 60 days before ICI initiation; subgroup analyses for within 30 days and 31–60 days before ICI2012.2–2018.5Nivolumab, pembrolizumab, and others (anti-PD-1/PD-L1/CTLA-4-based regimens)Cephalosporins; fluoroquinolones; beta-lactam/beta-lactamase inhibitors; carbapenems; glycopeptides; macrolides9
    Pinato et al.2019UKProspective multicenter cohort study14.6 monthsNSCLC subgroup from pan-cancer cohort119Mixed (mostly first-line metastatic)Broad-spectrum antibiotics within 30 days prior to ICI initiation (pATB) or during ICI (cATB)2015.1–2018.4Anti-PD-1/PD-L1 ICIsMainly β-lactam based10
    Ouaknine Krief et al.2019FranceRetrospective real-world cohort study500 days (IQR 401–599)NSCLC72Nivolumab used as 2nd-line or later therapyEarly use of antibiotics (EUA) = 2 months before to 1 month after ICI initiation2014.7–2017.9NivolumabOral or iv antibiotics, median duration 9.5 days, mainly β-lactams (36/51) and vancomycin11
    Mielgo Rubio et al.2019SpainRetrospective multicenter study6.5 monthsAdvanced NSCLC, PD-L1 ≥50%1211st-lineAntibiotics 2 months before to 1 month after ICI start2016.9–2019.3Pembrolizumab monotherapyQuinolones (40.7%), penicillins/derivatives (35.2%); iv 65.5%, oral 34.5%12
    Schett et al.2020Switzerland (two tertiary centers)Retrospective observational cohort5.5 months (95% CI 5–14)Advanced NSCLC (EGFR WT, ALK–)218Across 1st–4th-lines (majority 2nd-line)Within 2 months prior to ICI start2013.1–2017.12Nivolumab/pembrolizumab/atezolizumabβ-lactams, quinolones, macrolides (oral or iv)13
    Chalabi et al.2020Multiple countries (mainly Europe and America)Pooled retrospective analysis of randomized Phase II/III trials (OAK + POPLAR)19.2 monthsNSCLC1,512Mixed line30 days before ICI to 30 days after ICI (±30 days)-AtezolizumabQuinolones, penicillins, cephalosporins14
    Cortellini et al.2021Europe multicenterRetrospective multicenter real-world cohort21.8 monthsMetastatic NSCLC with PD-L1 ≥50%950First-line onlySystemic ATB within 30 days before first-line treatment initiation2017.1–2020.5Pembrolizumab monotherapy-15
    Hamada et al.2021JapanSingle-center retrospective study251.5 daysAdvanced NSCLC69Mixed lines (1L/2L/≥3L)Within 21 days before or after first anti-PD-1 dose2016.1–2019.12Nivolumab or pembrolizumabLevofloxacin, macrolides, cephems, TMP-SMX, carbapenems, tazobactam/piperacillin16
    Verschueren et al.2021BelgiumSingle-country real-world cohort-Stage IV NSCLC442Mixed lines: 1L, 2L, and 3LAntibiotic use within 30 days before and 30 days after treatment initiation-Nivolumab, pembrolizumab, atezolizumab-17
    Ren et al.2021ChinaPooled analysis of 5 tislelizumab monotherapy studies-NSCLC--Within 30 days of day 1-Tislelizumab-18
    Balado et al.2021SpainRetrospective study-Advanced/metastatic NSCLC, PD-L1 ≥50%491st-line immunotherapyATB+: systemic antibiotics within ±30 days of pembrolizumab start2017.7–2020.1Pembrolizumab monotherapy-19
    Castello et al.2021ItalyProspective registration + retrospective analysis12.4 months (9.7–15.2)NSCLC50Mixed-line12 patients received antibiotics 1 month before ICI initiation, and 11 patients received antibiotics within 1 month after ICI initiation (3 of whom received antibiotics in both time periods)2015.12–2019.5Nivolumab (62%), pembrolizumab (32%), nivolumab + ipilimumab (4%), atezolizumab (2%)β-lactam ± inhibitor (8 cases), quinolone (8 cases), rifaximin (1 case), glycopeptide (1 case), 2 cases unspecified20
    Geum et al.2021South KoreaRetrospective single-center cohort study-Advanced/recurrent NSCLC, predominantly adenocarcinoma (70%)140≥2nd-lineAny systemic antibiotic use from 30 days before nivolumab initiation until completion of nivolumab therapy2015.7–2018.6NivolumabVarious systemic antibiotics, mainly broad-spectrum agents21
    Ochi et al.2021Japan (9 institutions)Multicenter retrospective cohort study-Advanced/metastatic NSCLC531Any line of therapyWithin 2 months before or 1 month after starting ICI2015.12–2018.5PD-1/PD-L1 (nivolumab/pembrolizumab/atezolizumab)β-lactams most common, other classes (e.g., quinolones, macrolides) used at lower frequencies, not further detailed in the original report22
    Lu et al.2021Taiwan, ChinaRetrospective cohort-NSCLC3401st/2nd-line: 70%; ≥3rd-line: 30%Systemic antibiotics within 30 days before ICI2016.1–2019.3ICI: ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab (96% PD-(L)1 monotherapy)Broad-spectrum antibiotics: fluoroquinolones 39%, penicillins 38%, 1st/2nd-gen cephalosporins 33%, 3rd/4th-gen cephalosporins 30%, carbapenems 7%, macrolides 5%23
    Nyein et al.2022USARetrospective single-center study-NSCLC (Stage III/IV)256-From 60 days before ICI to 30 days after ICI2011.1–2017.3PD-1/PD-L1/CTLA-4 (monotherapy or combined with chemotherapy/targeted therapy)β-lactams, fluoroquinolones, macrolides, cephalosporins, tetracyclines; Most commonly used: levofloxacin (15), cefazolin (14), azithromycin (8)24
    Qiu et al.2022ChinaRetrospective study-NSCLC1481st-line: 48.0%, 2nd-line: 37.8%, 3rd-line: 14.2%ATB exposure was defined as use within 60 days before or after ICI initiation, and was further classified as 30–60 days before ICI, within 30 days before ICI, concurrent with ICI, within 30 days after ICI, and 30–60 days after ICI.2018.1–2021.6Camrelizumab, pembrolizumab, toripalimab, sintilimab, tislelizumab, nivolumab, durvalumabβ-lactams, quinolones, and their combination. Subclasses of β-lactams: Penicillins, cephalosporins, carbapenems25
    Joshi et al.2022USAProspective real-world cohort study-NSCLC136First-line only1 month before ICI2014.1–2019.5Pembrolizumab (1st-line, monotherapy or combined with chemotherapy)β-lactams, fluoroquinolones, macrolides, cephalosporins, tetracyclines26
    Stokes et al.2022USANested cohort studyNSCLC3,634pAbx (prior antibiotics): antibiotic exposure within 30 days before initiation of ICI2010–2018Nivolumab 59.1%, pembrolizumab 35.1% (total >94%)The most common were β-lactams (30.1%); other ATBs were not subdivided27
    Stokes et al.2022USANested cohort study-NSCLC3,634-cAbx (concurrent antibiotics): antibiotic exposure within 60 days after initiation of ICI2010–2018Nivolumab 59.1%, pembrolizumab 35.1% (total >94%)The most common were β-lactams (30.1%); other ATBs were not subdivided27
    Şen et al.2023TurkeyRetrospective cohort-NSCLC (Stage IV)9081.1% 1st-line, 18.9% 2nd-lineWithin 12 weeks after ICI initiation (primary analysis), the first 4/8 weeks were also analyzed-PD-1/PD-L1Outpatient: moxifloxacin, clarithromycin, amoxicillin-clavulanate; Inpatient: piperacillin-tazobactam, meropenem, vancomycin, colistin, TMP-SMX28
    Deng et al.2024ChinaRetrospective cohort study25.2 months (95% CI 22.99–27.34)NSCLC, locally advanced or metastatic (Stage Ⅲ–Ⅳ)3161st-line 238/316 (75.3%), ≥2nd-line 78/316 (24.7%); ATB group: 1st-line 108/134 (80.6%), ≥2nd-line 26/134 (19.4%); N-ATB group: 1st-line 130/182 (71.4%), ≥2nd-line 52/182 (28.6%)Within 30 days before ICI initiation (p-ATB) or during ICI treatment2018.01–2023.10PD-1/PD-L1 inhibitors: tislelizumab (138 cases), camrelizumab (85 cases), sintilimab (61 cases), pembrolizumab (14 cases), and other ICIs (18 cases).β-lactams (68 cases, 50.7%), quinolones (31 cases, 23.1%), quinolones + β-lactams (32 cases, 23.9%), macrolides (3 cases, 2.3%; β-lactams were further divided into BLBLI (β-lactam/β-lactamase inhibitor combinations, 54 cases, 40.3%) and non-BLBLI; common BLBLI included cefoperazone-sulbactam, mezlocillin-sulbactam, piperacillin-tazobactam, and amoxicillin-clavulanate.29
    Tamura et al.2024JapanRetrospective study [propensity score matching (PSM)]ABx: 45.9 months vs. Non-ABx: 47.2 monthsNSCLC201First-line only30 days before ICI2018.12–2020.12Pembrolizumab or atezolizumabβ-lactam/β-lactamase inhibitor combinations [AMPC/CVA 63.6%, PIPC/TAZ 15.2%, ABPC/SBT 9.1%], fluoroquinolones [LVFX, MFLX], sulfonamide/trimethoprim, macrolide [CAM], penicillin [AMPC], cephalosporin [CEZ], and glycopeptide [VCM]30
    Luo et al.2024ChinaProspective cohort study-EGFR+ advanced NSCLC74Mixed line2 months before and after ICI2019.3–2022.9PD-1/PD-L1 inhibitors-31
    Xie et al.2024China West China Hospital of Sichuan UniversityRetrospective cohort study-NSCLC accounted for 74.8% (≈472/631)472-Use of antibiotics within 3 months before initiation of ICI therapy2018.12–2023.6ICICephalosporins32
    Rousseau et al.2025FranceRetrospective cohort + target trial emulation-Advanced/metastatic NSCLC41,5291st-line therapy≥2 prescriptions of ATC J01 antibiotics, with prescription dates falling between 60 days prior to and 42 days after pembrolizumab initiation2015.1–2022.12Pembrolizumab monotherapy or pembrolizumab combined with chemotherapy (1st-line)Macrolides, penicillins, penicillins plus penicillinase inhibitors, β-lactams other than penicillin, sulfonamides, fluoroquinolones, and combinations of several antibiotic types33
    Ochi et al.2025JapanMulticenter retrospective study17.0 months (95% CI 15.8–18.2)NSCLC-1st-line therapy2 months before therapy to 1 month after therapy2018.12–2020.12Anti–PD-1, anti–PD-L1-34
    Hu et al.2025ChinaSingle-center retrospective33.79 monthsmNSCLC (Stage IV)199-±30 days before and after ICI2017.12–2021.10PD-1/PD-L1β-lactams 83.3% (penicillins ± β-lactamase inhibitors, cephalosporins, carbapenems), quinolones 57.8%, aminoglycosides, glycopeptides, and macrolides35
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