The molecular landscape of non-small cell lung
cancer (NSCLC) has been revolutionized by the discovery of
epidermal growth factor receptor (EGFR) mutations, which occur in
10-35% of Western patients and in ≤50% of Asian patients (1-3).
While EGFR tyrosine kinase inhibitors (TKIs) achieve unprecedented
initial response rates of 60-80%, the median progression-free
survival remains limited to 9-19 months due to the universal
development of acquired resistance (4-6).
Historically, resistance research has focused on tumor-autonomous
mechanisms, including secondary EGFR mutations (for example, T790M
and C797S), MET amplification and phenotypic transformation through
epithelial-mesenchymal transition (EMT) (5,7-9).
However, accumulating evidence reveals that dynamic
crosstalk between neoplastic cells and their microenvironment
contributes considerably to therapeutic evasion (10,11). The tumor microenvironment (TME),
comprising immune cells, cancer-associated fibroblasts (CAFs),
endothelial cells and extracellular matrix components, establishes
biochemical and physical barriers that compromise drug efficacy
through multiple mechanisms (12,13).
The present comprehensive review systematically
examines the molecular biology of IL-6 signaling networks in
EGFR-driven tumorigenesis, the multidimensional role of IL-6 in
sculpting therapy-resistant TME architectures, preclinical evidence
for IL-6 pathway inhibition in resensitizing refractory tumors and
current clinical challenges and future directions for
biomarker-driven combination therapies. We hypothesize that
targeting IL-6-mediated crosstalk between tumor cells and their
ecological niche represents a promising strategy to overcome
microenvironment-mediated resistance.
The IL-6 gene, located on chromosome 7p21, encodes a
184-amino-acid protein. Structurally, IL-6 consists of four long
α-helices and three loops at their junctions, which maturely form
following proteolytic cleavage of its signal peptide (22). IL-6 signaling is mediated by a
receptor complex consisting of IL-6, the IL-6 receptor α subunit
(IL-6Rα) and glycoprotein 130 (gp130) (23). Specifically, IL-6 first binds to
membrane-bound IL-6Rα, an 80 kDa protein featuring an extracellular
IL-6 binding domain and a minimal cytoplasmic domain. This
IL-6/IL-6Rα complex subsequently recruits gp130 (an IL-6 signal
transducer), initiating intracellular signal transduction (24). The structural organization of IL-6
is shown in Fig. 1.
IL-6, a pleiotropic inflammatory cytokine
predominantly secreted by fibroblasts, myeloid-derived suppressor
cells (MDSCs), tumor-associated macrophages (TAMs) and tumor cells
(25-28), signals through four distinct
molecular pathways. The classical and trans-signaling pathways
constitute the two primary modes of IL-6 signal transduction
(29-31), with two additional modalities more
recently characterized (32,33). All IL-6-related cytokine receptor
complexes (IL-6/IL-6R/gp130) activate an intracellular signal: The
JAK/STAT pathway. Furthermore, gp130 phosphorylation triggers
secondary downstream pathways, including MAPK-ERK and PI3K-Akt,
which synergistically amplify oncogenic signaling (34). The nuclear translocation of
activated STAT proteins induces the transcription of
tumor-promoting genes associated with proliferation, metastasis and
immune evasion (35). Apart from
its canonical transcriptional roles in maintaining stemness,
survival, metastatic potential and immune evasion across
malignancies (36-40), cytoplasmic STAT3 drives tumor
progression through non-transcriptional mechanisms. These include
metabolic reprogramming and direct interactions with cytosolic
signaling effectors, which collectively sustain tumor expansion
(41,42). Mechanistically, through classical
membrane-bound receptor signaling and trans-signaling via soluble
IL-6R, IL-6 activates downstream JAK/STAT3, MAPK and PI3K/AKT
pathways, driving the pro-survival signaling, stemness maintenance
and immune evasion of tumor cells (43-46) (Fig.
2).
IL-6 signaling has a key influence on the prognosis
of patients with NSCLC. Accumulating evidence has demonstrated that
IL-6 is overexpressed across multiple malignancies and is
associated with tumor progression (47,48). Mechanistically, IL-6 enhances
cancer stemness properties (45,46), whereas pharmacological inhibition
of the IL-6/JAK/STAT3 axis suppresses tumorigenic potential
(45,49). Notably, IL-6 synergistically
interacts with EGFR signaling to drive NSCLC progression
(50). In EGFR-mutant
NSCLC cells, treatment with EGFR-TKI paradoxically activates
compensatory Src/IL-6/STAT3 signaling, thereby sustaining tumor
cell survival (51). Preclinical
studies have shown that IL-6 blockade markedly reduces tumor burden
(52), while JAK1/2 inhibitors
(for example ruxolitinib) effectively suppress the growth of
EGFR-mutant tumors (53).
Collectively, these findings position IL-6 as a key
molecular nexus bridging tumorigenesis and clinical prognosis in
NSCLC. The IL-6/JAK/STAT3 signaling cascade operates independently
of the mutational status of EGFR, exerting pleiotropic effects on
tumor cell behavior through both canonical and non-canonical
mechanisms.
The majority of patients treated with EGFR-TKI
develop acquired resistance within 9 to 14 months of therapy
(5). Accumulating evidence
highlights the key role of IL-6 in shaping immunosuppressive
processes within the TME (63).
Furthermore, increasing data indicate a clear association between
resistance to EGFR-TKI and IL-6 signaling. IL-6 orchestrates TME
immunosuppression, leading to resistance to EGFR-TKI through
multiple mechanisms (Fig. 3).
Elevated IL-6 is consistently associated with
adverse clinical outcomes in EGFR-mutant patients with NSCLC
treated with EGFR-TKI (64).
Specifically, IL-6 positivity by immunostaining (found in 46% of
patients in one cohort) associates with notably worse PFS (43). Furthermore, higher pretreatment
serum IL-6 levels predict reduced PFS and overall survival (OS)
(65). This prognostic link
extends to the point of acquired resistance, where IL-6 levels are
substantially increased upon resistance development in both
gefitinib- and osimertinib-treated patients. Notably, after
gefitinib resistance emerges, patients with markedly elevated IL-6
have markedly shorter OS compared with those with lower levels
(44). Collectively, these
clinical observations substantiate that IL-6 plays a pivotal
regulatory role in both outcomes of and therapeutic resistance
mechanisms in EGFR-mutant patients with NSCLC.
Investigative studies reveal that IL-6 plays a
pivotal role in conferring EGFR-TKI resistance through direct
effects on tumor cells (66-68). Constitutive activation of the
IL-6/JAK2/STAT3 signaling axis is observed in resistant cellular
models (69). Mechanistically,
this cascade mediates resistance via autocrine IL-6 production and
STAT3 positive feedback activation, facilitating tumor cell
survival and proliferation both in vitro and in vivo
(67,70). Complementary preclinical
investigations reveal that pharmacological inhibition of this
signaling axis restored EGFR-TKI sensitivity in murine models,
providing therapeutic proof-of-concept (68).
Furthermore, IL-6 contributes to acquired resistance
by driving tumor cell-intrinsic EMT progression. Molecular analyses
show that IL-6 suppresses E-cadherin and transcriptionally
upregulates mesenchymal markers such as Snail and vimentin
(71). The self-sustaining
IL-6/IGF-1R/STAT3 autocrine loop has been identified as a key EMT
driver (72), with TGFβ cytokine
coactivation shown to potentiate IL-6 pathway signaling and
subsequent EMT progression. Notably, metformin administration has
been shown to suppress EGFR-TKI-resistant xenograft tumorigenesis
through dual mechanisms involving a reduction in IL-6 secretion and
a reversal of the EMT phenotype (71). These studies illustrate the key
role that IL-6 carries out in resistance to EGFR-TKI mediated by
EMT, the IL-6/JAK/STAT3 signaling pathway and other mechanisms,
thereby providing potential treatment options against resistance.
In addition, IL-6 can regulate transcription factors governing DNA
repair fidelity and cell cycle checkpoint control, potentially
impairing genomic replication accuracy (73,74). These direct actions of IL-6 on
tumor cells underscore its importance in survival, proliferation
and resistance development.
Lymphocytes are fundamental to antitumor immunity,
yet EGFR-TKI resistance is frequently characterized by the
depletion of CD8+ T cells and the expansion of
immunosuppressive subsets (75,76). IL-6 acts as a central orchestrator
of this T-cell dysfunction through distinct molecular mechanisms
(52,77-79). Mechanistically, the IL-6 signaling
exerts dual immunomodulatory effects by suppressing key cytotoxic
mediators (IFN-γ, GM-CSF and CXCL9/10) while concurrently inducing
IL-10 secretion and Th2/Th17-polarizing factors, thereby
reprogramming CD8+ T-cell differentiation toward
dysfunctional states (80). In
EGFR-TKI-resistant NSCLC microenvironments, IL-6-mediated
downregulation of granzyme B expression considerably impairs
CD8+ T-cell cytotoxic capacity, establishing a direct
association between cytokine signaling and immune effector
dysfunction (81). Importantly,
IL-6 drives T-cell exhaustion by engaging the programmed cell
death-1 (PD-1)/PD-ligand (PD-L1) checkpoint axis. In the TME,
macrophage-derived IL-6 promotes the membrane presentation of PD-1
on T cells via the Rab37/IL-6/STAT3 axis (82). Simultaneously, oncogenic
IL-6/JAK/STAT3 signaling in EGFR-mutant tumor cells
transcriptionally activates PD-L1 expression, thereby conferring a
survival advantage through immune escape (83,84).
NK cells serve as a primary innate defense, but
their surveillance capability is severely compromised in the
EGFR-TKI-resistant microenvironment. Distinct from its effects on T
cells, IL-6 blunts NK cell effector function by targeting
activating receptors. Tumor-derived IL-6 triggers STAT3
phosphorylation in NK cells, which transcriptionally downregulates
surface expression of NKp30 and NKG2D, thereby desensitizing
resistant cells to NK-mediated lysis (81,92). Additionally, STAT3 binding to the
IFN-γ promoter region directly antagonizes IFN-γ production
(93). This IL-6-dependent
downregulation of recognition receptors and cytokines establishes a
specific mechanism of innate immune evasion during therapy.
CAFs are key stromal components that drive tumor
progression through the secretion of soluble factors, notably IL-6
and TGF-β, orchestrating pro-tumorigenic processes such as
angiogenesis, invasive growth and metastatic dissemination
(94-98). CAFs themselves represent a notable
source of IL-6 within the TME. IL-6 directly impacts CAF behavior,
stimulating the proliferation of normal fibroblasts and inducing a
CAF-like phenotype (99,100). Pathophysiological investigations
have revealed that bidirectional communication between EGFR-mutant
NSCLC cells and CAFs sustains constitutive activation of the
IL-6/JAK/STAT3 cascade in malignant cells, thereby conferring
therapeutic resistance to EGFR-TKI across preclinical in
vitro and in vivo models (67,101). Targeting the paracrine
IL-6/JAK/STAT3 loop between fibroblasts and tumor cells (67) or employing agents such as
tranilast that decrease CAFs-derived IL-6, effectively abrogates
CAFs-mediated resistance (101).
Beyond IL-6, CAFs also express other cytokines such as oncostatin-M
(OSM). A preclinical study showed that combination therapy with
EGFR-TKI and JAK1 inhibitors (for example, filgotinib) potently
inhibits the fibroblast-activated OSMRs/JAK1/STAT3 axis, disrupting
stroma-driven pathway crosstalk to prevent adaptive drug resistance
(102).
TAMs, which predominantly exhibit M2 polarization
with a few M1 subpopulations, serve as pivotal mediators of tumor
progression, metastatic dissemination and formation of an
immunosuppressive microenvironment (103,104). In EGFR-TKI-resistant tissues,
IL-6/JAK/STAT3 signaling drives the polarization of TAMs toward a
protumor M2 phenotype (105).
IL-6/JAK/STAT3 signaling orchestrates three cardinal TAM features,
chemotactic migration, survival maintenance and M2 polarization,
which are characterized by arginase-1 (Arg1) overexpression coupled
with inducible nitric oxide synthase downregulation (106). Concurrently, TAMs can also
secrete IL-6 to promote lung cancer progression and metastasis
(107,108). Previous mechanistic insights
reveal that phase separation of YY1 transcriptional complexes in M2
TAMs enhances chromatin accessibility at IL-6 regulatory regions,
amplifying IL-6 transcription and creating a self-reinforcing loop
(109). Functional crosstalk
analyses also demonstrate that TAM-derived IL-6 activates
COX-2/PGE2 cascades in adjacent tumor cells, inducing EMT (110). Thus, IL-6 coordinates a dual
mechanism in the myeloid compartment: Promoting M2-mediated tissue
remodeling and enforcing intercellular communication.
MDSCs are heterogeneous progenitors that markedly
contribute to therapeutic refractoriness (111). Elevated cytokine levels in the
serum of patients with EGFR-TKI-resistant NSCLC associate with MDSC
expansion and poor prognosis (112,113). IL-6 serves as a master regulator
of MDSC biology through specific epigenetic and metabolic
reprogramming. Mechanistically, STAT3-mediated chromatin remodeling
at the Arg1 promoter drives the immunosuppressive polarization of
MDSCs (114-120). Concurrently, IL-6 primes MDSCs
to undergo metabolic rewiring (enhanced glycolysis/oxidative
phosphorylation) and suppresses their antigen presentation
machinery (121). These
functional alterations collectively potentiate MDSC-mediated T-cell
suppression, positioning the IL-6 axis as a strategic target to
dismantle the myeloid barrier in resistant tumors.
Taken together, IL-6 serves as a pivotal nexus
connecting EGFR-TKI resistance with the immunosuppressive TME.
Under persistent selective pressure from EGFR-TKI, surviving tumor
cells exhibit markedly upregulated IL-6 secretion. Once released
into the microenvironment, IL-6 triggers sustained activation of
the intrinsic JAK/STAT3 pathway via either classical or
trans-signaling modes. This establishes a self-reinforcing
autocrine loop that directly orchestrates resistance-associated
phenotypes, including EMT and the expression of pro-survival genes.
Importantly, IL-6 also actively induces and sustains an
immunosuppressive TME. This landscape is characterized by the
functional impairment of effector T cells and NK cells, coupled
with the recruitment and polarization of suppressive subsets such
as Tregs, TAMs and MDSCs. Notably, this remodeling is not a
unidirectional process; immunosuppressive cells and stromal
components (for example, TAMs and CAFs) also serve as prolific
sources of IL-6, thereby amplifying the signaling cascade.
Paracrine IL-6 from these accessory cells feeds back to the tumor
cells, further fueling downstream pathways to sustain tumor growth
and the resistant phenotype. Within the context of
EGFR-mutant NSCLC, this reciprocal 'crosstalk' and mutual
reinforcement among tumor, immune and stromal cells constitute a
vicious cycle that drives EGFR-TKI resistance. Consequently, IL-6
functions as a key bridge, inextricably linking intrinsic TKI
tolerance mechanisms with complex immune evasion strategies to
establish a synergistic resistance axis. Targeting this IL-6-driven
axis thus provides a compelling theoretical rationale for
developing novel combination therapeutic strategies to overcome
EGFR-TKI resistance.
Multiple preclinical studies and clinical trials
examining IL-6 pathway blockade in EGFR-TKI-resistant NSCLC have
been summarized in Table I
(44,53,68,69,101,102,122-128), some of which are aforementioned.
The majority of these studies have focused only on the production
of IL-6 and its signaling pathway.
Siltuximab (CNTO328), an IL-6 neutralizing antibody,
inhibited the proliferation of H1650 cells, whereas the combination
of siltuximab and erlotinib resulted in more pronounced inhibition
of tumor growth in a mouse model (122). In EGFR-mutant tumor cells
that are resistant to gefitinib due to IL-6 induction, miR-206
directly targets the 3'-UTR of intracellular IL-6 messenger RNA to
block IL-6/JAK/STAT3 signaling, thereby restoring gefitinib
sensitivity (123). Compared
with no treatment, the addition of IL-6 to erlotinib-sensitive
cells increased drug resistance. Additionally, the presence of IL-6
did not prevent the restoration of cell sensitivity to erlotinib by
treatment with P6 (a JAK1/2 inhibitor) (68). The JAK inhibitor AZD1480 showed
anticancer and antiangiogenic effects (129,130). AZD1480 alleviated
sevoflurane-induced lung metastasis by disrupting the
IL-6/JAK/STAT3 pathway (131).
Furthermore, in mice bearing EGFR-driven lung cancer,
AZD1480 showed marked antitumor activity and extended survival time
(124). However, erlotinib and
momelotinib (JAK1/2 and TBK1 inhibitors) did not appear to provide
a greater benefit compared with erlotinib monotherapy in
EGFR-mutated patients with NSCLC (125).
Ibrutinib consistently and effectively suppressed
the levels of phosphorylated STAT3, which is a powerful inhibitor
of IL-6 and laminin α5/FAK signaling. The combination of ibrutinib
and osimertinib can reverse resistance to osimertinib and inhibit
tumor growth in xenografts (44).
Similar findings have been reported for AZD9150 (an inhibitor of
STAT3), in which systemic treatment of mice bearing PC-9 tumors
with AZD9150 led to the almost complete suppression of tumor growth
(126). HKB99 (a PGAM1
allosteric inhibitor) disrupted IL-6/JAK/STAT3 signaling by
decreasing the level of phosphorylated (p)-STAT3. Additionally,
when combined with osimertinib, HKB99 exerted a synergistic
tumoricidal effect and markedly restored the sensitivity to
EGFR-TKI (69). A cell experiment
revealed that WP1066, a known STAT3 inhibitor, could cause H1650
cells to undergo apoptosis, with an inhibitory effect on tumor
growth (128). When EGFR-TKI and
TPCA-1, a dual inhibitor of both IKKs and STAT3, are coupled
together, EGFR-mutated NSCLC is more sensitive to gefitinib
(127).
Homoharringtonine possesses anticancer properties,
as demonstrated by its ability to reversibly inhibit the
IL-6-induced phosphorylation of STAT3 at the Tyr705 site in a mouse
model of EGFR-TKI resistance (132). A naturally occurring chemical
substance called polyphyllin I (PPI) has anticancer properties and
reduces the activation of the IL-6/STAT3 pathway in
erlotinib-resistant cells. The combined use of PPI and EGFR-TKI
reduces tumor growth and reverses acquired resistance in xenografts
(133).
However, following the onset of EGFR-TKI resistance,
therapeutic strategies targeting the IL-6/JAK/STAT3 pathway alone
often yield suboptimal results. One of the primary hurdles in
achieving robust clinical efficacy is the inherent cytokine
redundancy within the TME. IL-6 belongs to a larger family of
cytokines, including leukemia inhibitory factor, OSM and IL-11, all
of which converge on the common signal-transducing receptor
subunit, gp130 (48,134-136). Furthermore, the IL-6/JAK/STAT3
axis operates as an integral part of a complex, interconnected
network. Tumor cells frequently develop compensatory mechanisms to
bypass specific pathway blockade. For instance, the inhibition of
JAK/STAT3 signaling may trigger compensatory activation of the
PI3K/AKT or MEK pathways, enabling cancer cells to sustain survival
and proliferation, thereby limiting therapeutic efficacy (137,138). Clinical data (NCT00841191) from
trials of Siltuximab (a chimeric anti-IL-6 monoclonal antibody)
have shown that while systemic CRP levels (a surrogate for IL-6
activity) are successfully suppressed, intratumoral p-STAT3 levels
often persist, suggesting that the 'gp130-JAK-STAT3' hub remains
fueled by alternative ligands. This signaling bypass renders the
selective blockade of a single cytokine insufficient to dismantle
the pro-tumorigenic niche, necessitating a shift toward targeting
the shared gp130 receptor or the downstream STAT3 transcription
factor.
Immunotherapy has been among the greatest advances
in previous years for the treatment of solid tumors, including
NSCLC (139,140). EGFR-TKI resistance upregulates
PD-L1 expression in NSCLC, providing a theoretical basis for
immunotherapy (Table II).
However, negative results from large clinical studies suggest that
patients who develop resistance to EGFR-TKI have difficulty
benefiting from treatment with immunotherapy alone or immunotherapy
combined with chemotherapy (141-143). This poor response to
immunotherapy is largely attributed to an immunosuppressive TME.
Here, IL-6 carries out a pivotal role. IL-6 levels are
substantially increased upon resistance development in
EGFR-TKI-treated patients (44,65). IL-6 may orchestrate multifaceted
immunomodulatory effects within the TME of EGFR-mutant NSCLC
through the following mechanisms: First, suppression of antitumor
immunity: IL-6 exerts inhibitory effects on effector T cells, NK
cells and DCs, with experimental evidence suggesting that
IL-6/JAK/STAT3 pathway activation in these immune subsets likely
drives downregulation of the antitumor response (144-146). Second, promotion of
immunosuppressive networks: Concurrently, IL-6 enhances the
expansion and function of immunosuppressive cell populations,
including MDSCs and Tregs, while polarizing macrophages toward the
M2 phenotype (147,148). Third, immune checkpoint
modulation: IL-6 further disrupts immune-tumor crosstalk by
upregulating PD-1/PD-L1 expression, thereby fostering an
immune-evasive niche (149,150). These effects contribute to a
highly immunosuppressive TME, which in turn may mediate resistance
to EGFR-TKI. The inhibition of IL-6/JAK/STAT3 signaling can also
affect the TME and has implications for antitumor immunity.
Consequently, dual targeting of IL-6 signaling and the PD-1/PD-L1
axis represents a promising therapeutic approach to overcome
resistance to EGFR-TKI in NSCLC.
Currently, there are Phase I and II clinical trials
evaluating the efficacy and safety of the combination of anti-IL-6R
and anti-IL-6 with immunotherapy in patients with NSCLC (Table SI). The CANOPY-1 trial
demonstrated that elevated baseline plasma IL-6 levels associate
with shorter OS in immunotherapy-treated patients with NSCLC
(149). Similarly, longitudinal
increases in IL-6 levels during PD-1/PD-L1 blockade were associated
with diminished therapeutic responses in NSCLC cohorts (82). Furthermore, elevated plasma
cytokine profiles, including those of IL-6, TNF and IL-8, have been
implicated in immunotherapy resistance (151). Preclinical studies substantiate
these findings, showing that inhibition of the IL-6 pathway
augments immunotherapy efficacy through immune cell modulation
within the TME (152,153). For instance, dual administration
of anti-IL-6 and anti-PD-1 antibodies in pancreatic cancer murine
models enhanced antitumor activity and promoted T lymphocyte
infiltration (153).
Analogously, coordinated blockade of IL-6 and PD-1/PD-L1 signaling
in melanoma models upregulates the expression of T-cell-recruiting
chemokines and increases the infiltration of IFN-γ-producing
CD4+ T cells, yielding synergistic antitumor effects
(152). Notably, retrospective
analyses revealed that patients with NSCLC with low baseline IL-6
levels in plasma or tumor tissues derived greater clinical benefit
from immunotherapy. Preclinically, dual targeting of IL-6 and
immune checkpoints attenuated tumor growth and improved survival in
NSCLC-bearing mice. Mechanistically, inhibition of IL-6 expression
increases CD8+ T-cell infiltration while reducing the
numbers of PD1+CD8+-exhausted T cells and M2
macrophages within the TME (52,82). Moreover, IL-6 blockade sensitized
tumors to immunotherapy through the activation of T and NK cells in
EGFR-mutant genetically engineered mouse model (81). Depletion of IL-6 restored the
cytotoxic potential of NK cells in EGFR-TKI-resistant tumors
(81). Collectively, these
findings suggest that IL-6 is a rational immunomodulatory target
for increasing immunotherapy efficacy in EGFR-TKI-resistant NSCLC.
However, definitive clinical validation through dose-optimized
trials remains imperative.
The hyperactivation of STAT3, a downstream effector
of IL-6, a key transcriptional regulator for angiogenic factors,
most notably vascular endothelial growth factor, thereby
facilitating the neovascularization required for tumor maintenance
and dissemination (154,155). Consequently, the IL-6/JAK/STAT3
axis acts as a pro-angiogenic signaling node; its activation not
only promotes tumor cell survival but also remodels the vascular
microenvironment. Preclinical evidence supports this strategy: the
JAK inhibitor AZD1480 has demonstrated dual anticancer and
anti-angiogenic properties (129,130). Furthermore, in murine models of
EGFR-driven lung cancer, AZD1480 treatment elicits marked antitumor
activity and notably extended survival (124), underscoring the potential of
targeting this axis to suppress both tumor growth and pathological
angiogenesis.
In conclusion, the IL-6/JAK/STAT3 signaling axis
represents a pivotal mechanism of adaptive resistance in
EGFR-mutant NSCLC, orchestrated through intricate crosstalk
between tumor cells, stromal components and infiltrating immune
subsets within the TME, leading to improved immunotherapy efficacy.
While preclinical data have demonstrated that IL-6 blockade can
restore sensitivity to EGFR-TKI and potentially sensitize tumors to
immunotherapy, the translation of these findings into clinical
practice faces hurdles. Substantial preclinical and clinical
research will be needed to determine the exact efficacy of this
strategy.
Currently, large-scale Phase III clinical trials
specifically evaluating IL-6/JAK/STAT3 inhibitors in EGFR-mutant
NSCLC populations are lacking. The majority of existing evidence is
derived from broader NSCLC cohorts or early-phase studies. A
considerable challenge observed in immunotherapy trials, such as
CANOPY-1, is the variable efficacy of cytokine blockade,
underscoring the necessity of identifying specific responder
populations. Furthermore, pharmacological interactions pose a
translational barrier; for instance, elevated plasma IL-6
concentrations have been associated with reduced metabolic activity
of osimertinib, potentially altering drug exposure and efficacy
(156). This highlights the need
for rigorous pharmacokinetic evaluations when combining IL-6
inhibitors with third-generation EGFR-TKI.
The lack of robust biomarkers for patient
stratification remains a major limiting factor. Plasma IL-6 and
soluble IL-6R levels have shown prognostic value, where elevated
concentrations associate with shorter OS in patients treated with
EGFR-TKI or immunotherapy (44,52,149). Tissue p-STAT3 levels serve as a
direct indicator of downstream signaling activation. validating
these biomarkers in prospective trials is essential to transition
from general cytokine inhibition to precision medicine
strategies.
Despite the compelling preclinical rationale
connecting IL-6 signaling to EGFR-TKI resistance, several key
knowledge gaps must be bridged to facilitate successful clinical
translation. First, the spatiotemporal heterogeneity of the IL-6
pathway remains elusive. It is imperative to determine whether the
dominant cellular sources of IL-6, and the intensity of signaling,
vary between primary tumors and metastatic sites or evolve
dynamically from the initial TKI-sensitive phase to the onset of
acquired resistance (67,81). Second, the optimal timing of
intervention is currently undefined. Future studies must
distinguish whether IL-6 blockade yields superior outcomes as an
upfront prophylactic strategy to delay resistance or as a salvage
regimen upon disease progression. Third, the choice of optimal
therapeutic drugs warrants comparative investigation. The
efficacy-toxicity profiles of directly neutralizing IL-6, blocking
IL-6R, inhibiting JAK, vs. targeting STAT3 downstream, remain to be
systematically evaluated in the context of EGFR-mutant NSCLC (see
Table I for preclinical agents).
Finally, translational success will depend on a holistic
understanding of the dynamic crosstalk between IL-6 and other
oncogenic pathways, as well as the optimization of dosing schedules
and patient selection to manage potential side effects. Addressing
these complexities is essential to transform IL-6 inhibition from a
theoretical concept into a precise, effective combination strategy
for EGFR-mutant NSCLC.
Not applicable.
QW, CH and YZ wrote the manuscript and designed all
the figures and tables in consultation with the other authors. HZ,
CQ and ST contributed to the writing and editing of the manuscript.
WL, YL and PT developed the concept and reviewed and edited the
manuscript. All the authors read and approved the final version of
the manuscript. Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
This work was supported by the National Natural Science
Foundation of China (grant nos. 82473213, 82470099 and
92159302).
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