The Role of Nuclear Factor-κB in Cancer Immunity and Immunoediting

Introduction

Cancer is a complex, multi-step disease driven by the accumulation of genetic mutations, including the activation of proto-oncogenes and the inactivation of tumor suppressor genes. ¹ The loss of tumor suppressor function plays a critical role by allowing cells to bypass natural aging mechanisms like senescence, enabling them to acquire an immortal phenotype that, when combined with further genetic alterations, can lead to malignancy. ² However, genetic transformation alone is not sufficient. Emerging tumor cells must also evade the body’s immune system, which is equipped to recognize and eliminate abnormal cells. This vigilant immune activity initiates what is known as immune surveillance, a process that targets and destroys nascent tumor cells before they can establish disease.^2,3 Despite this defense, a subset of genetically unstable tumor cells may survive immune elimination, especially their proliferation is temporarily kept in check by immune pressure. ⁴ Over time, these surviving cells may accumulate additional mutations that allow them to escape immune detection and thrive. ⁴ The capacity of tumors to evade immune responses is now considered a fundamental hallmark of cancer.

The concepts of cancer immunosurveillance and immunoediting demonstrated about the immune system’s role, not only in detecting and eliminating cancer cells but also its limitations. ⁵ Cancer immunoediting, a dynamic process that describes the dual role of the immune system in both suppressing and promoting tumor development. It encompasses three interconnected phases: elimination, where immune cells detect and destroy cancer cells; equilibrium, a state of balance in which residual tumor cells persist but are kept under control; and escape, where tumors acquire the ability to grow unchecked by the immune system. As tumors expand and progress to detectable stages, they begin to release soluble factors that further manipulate the tumor microenvironment (TME) to their advantage, contributing to immune evasion and disease advancement. The immunoediting model has reshaped our understanding of how the immune system interacts with cancer, highlighting both its protective and permissive roles. This paradigm is central to developing next-generation immunotherapeutic strategies aimed at tipping the balance back in favor of anti-tumor immunity.^4-6

Chronic inflammation is now recognized as one of the defining hallmarks of cancer, with profound regulatory roles in tumor initiation, progression, and the suppression of anti-tumor immunity. ⁷ Among the key molecular players in this context is the proinflammatory transcription factor Nuclear Factor κB (NFκB), which has long been implicated in the development and advancement of cancer. ⁸ NFκB’s role in cancer is complex and context-dependent. In immune cells, it can act as both a promoter and suppressor of tumor development, depending on the stage and nature of the immune response. ⁹ During the early phases of tumor detection, particularly the elimination stage, NFκB activation via various receptor signaling pathways helps stimulate anti-tumor immunity through cytokine release and the activation of cytotoxic functions in immune cells. ¹⁰ However, as the tumor adapts and evolves, the role of NFκB begins to shift. In the transition from immune equilibrium to immune escape, NFκB contributes to a pro-tumorigenic environment by reprogramming immune cell behavior, often suppressing their anti-tumor functions. It also drives the expression of several tumor-promoting factors, including growth factors, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-9 (MMP9), all of which support tumor growth, angiogenesis and metastasis. ⁹

In this review, we explore the dual role of NFκB in regulating immune cell behavior during three phases of cancer immunoediting. We examine how NFκB signaling intersects with key molecular and cellular events that govern immune surveillance, the elimination of transformed cells, and the eventual immune escape of malignant cells. Finally, we discuss the broader implications of targeting NFκB as a potential strategy for enhancing cancer immunotherapy and improving clinical outcomes.

An Overview of NFκB Activation

The NFκB family of transcription factors plays a central role in regulating immune responses, inflammation, and cancer progression. This family comprises five key proteins—p65 (RelA), RelB, c-Rel, NFκB1 (p50/p105), and NFκB2 (p52/p100), which function by forming various homo- or heterodimeric complexes. ¹¹ All members share a highly conserved N-terminal Rel Homology Domain (RHD) of approximately 300 amino acids, which is crucial for dimerization, DNA binding, nuclear localization, and interaction with inhibitory IκB proteins. ¹² Based on their ability to activate transcription, NFκB proteins can be categorized into two groups. Only RelA (p65), RelB, and c-Rel contain a C-terminal transactivation domain (TAD), which enables them to directly initiate gene transcription ¹¹ (Figure 1). Notably, RelB is functionally distinct, requiring not only its TAD but also a leucine zipper domain at the N-terminus for full transcriptional activity. ¹¹ The p105 and p100 proteins serve as precursors and are processed into p50 and p52, respectively. Interestingly, not all NFκB dimers are transcriptionally active; p50 and p52 homodimers, for instance, can suppress κB-dependent gene expression by competing with the active dimers for DNA binding or by recruiting transcriptional repressors such as histone deacetylases to gene promoters. ¹³ OPEN IN VIEWER

In their resting state, NFκB dimers are sequestered in the cytoplasm through interactions with IκB proteins. ¹⁰ These interactions are mediated by ankyrin repeat motifs within the IκBs, which bind to the RHD of NFκB proteins and prevent their nuclear translocation. NFκB transcription factors are activated through two major signaling pathways: the canonical (classical) and noncanonical (alternative) pathway.^14,15 These pathways are triggered by distinct stimuli and regulate different aspects of immune function. The canonical pathway is typically activated by pro-inflammatory cytokines, antigen receptor signaling in B and T cells, and pattern-recognition receptors (PRRs) that detect microbial components. ¹⁶ Activation of this pathway relies on the IκB kinase (IKK) complex, which is composed of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit known as NEMO (NFκB essential modulator or IKKγ). Upon activation, the IKK complex phosphorylates IκB proteins, targeting them for proteasomal degradation. This process frees NFκB dimers—most commonly p50/RelA or p50/c-Rel, which then translocate rapidly and transiently into the nucleus to initiate gene transcription^11,17 (Figure 2).OPEN IN VIEWER

In contrast, the noncanonical pathway responds to a specific set of signals, primarily from members of the tumor necrosis factor receptor (TNFR) superfamily, such as lymphotoxin-β-receptor (LTβR), B-cell activating factor (BAFF) receptor (BAFFR), cluster of differentiation-40 (CD40), and receptor activator of nuclear factor κ-B (RANK). This pathway depends on the stabilization and activation of NFκB-inducing kinase (NIK), which in turn drives the processing of the p100 precursor into p52. The resulting p52/RelB dimers then translocate into the nucleus, where they modulate gene expression in a more sustained and regulated manner compared to the canonical route^15,18 (Figure 2). Both signaling pathways play critical roles in shaping innate and adaptive immune responses within the tumor immune microenvironment. ¹⁰

NFκB in Tumor Microenvironment: From Immune Surveillance to Immune Evasion

Cancer is the battle between rapidly evolving tumor cells and the vigilant immune system. The Immune system recognize and eliminate cancer cells through a process known as immune surveillance, which relies on the detection of tumor-specific antigens.^19,20 However, tumors often manage to persist and evolve despite this surveillance, a phenomenon explained by the concept of cancer immunoediting. The process describes how the immune system applies selective pressure, eliminating highly immunogenic tumor cells while inadvertently allowing less immunogenic variants to survive and proliferate ⁶ (Figure 3).OPEN IN VIEWER

Adding to this complexity is the role of inflammation and its key regulator, NFκB. Chronic inflammation within the TME, often fueled by cytokines and chemokines produced by both tumor and immune cells, can significantly shape the trajectory of cancer. ²¹ NFκB, a central transcription factor in inflammatory signaling, has long been linked to tumorigenesis.^8,9 It regulates genes involved in survival, proliferation, and metastasis, and its activation can tip the balance either toward tumor suppression or promotion. In immune cells, it can exert both pro- and anti-tumoral effects, depending on the context and cellular interactions within the TME.^9,10,13 This dual behavior presents a significant challenge: why does NFκB drive tumor progression in some cases while supporting anti-tumor immunity in others?

To unravel this paradox, it is essential to address NFκB’s influence across a broad spectrum of immune cells. These include anti-tumor effectors such as T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells, as well as immunosuppressive populations like tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), T-regulatory (Treg) cells, and B-regulatory (Breg) cells.^7,22 Each of these cell types plays a distinct role in shaping immune responses within the TME. Here, we’ve systematically explained the role of NFκB in different immune cells involved in phases of cancer immunoediting.

NFκB and Dysregulation of Hematopoiesis during Cancer

Hematopoietic stem and progenitor cells (HSPCs) give rise to all blood and immune cell lineages. ¹⁷⁶ Increased circulating HSPCs, particularly granulocyte–monocyte progenitors (GMPs), multipotent progenitors (MPPs), and hematopoietic stem cells (HSCs), have been observed in patients across multiple cancers, correlating with immunosuppressive phenotypes, higher tumor grade, and poor prognosis.^176,177 Within the TME, HSPCs undergo myeloid-biased differentiation, expanding tumor-associated myeloid populations such as MDSCs, neutrophils, and macrophages, driven by inflammatory cytokines including GMCSF, GCSF, IL6, and IL1. ¹⁷⁸

Animal studies further support these observations. In MMTV-PyMT transgenic mice, expansion of HSCs, MPPs, and GMPs precedes the accumulation of immunosuppressive myeloid cells, mediated by GCSF.^176,179 Similarly, mice bearing MC57 fibrosarcoma or B16-F10 melanoma exhibit HSPC expansion and myeloid-biased hematopoiesis.^176,180 MDSCs suppress anti-tumor immunity through multiple mechanisms, with NFκB playing a key role in their tumor-promoting functions.^131,181,182

In acute myeloid leukemia (AML), HSCs in leukemic bone marrow exhibit elevated early growth response-3 (EGR3), which induces cell cycle arrest and functional suppression; NFκB regulates EGR3 expression.^183-185 Pharmacologic inhibition of NFκB selectively kills AML cells while sparing normal CD34⁺CD38^- bone marrow cells, highlighting its importance in AML survival. ¹⁸⁶ In chronic myeloid leukemia (CML), TME-derived TNFα activates NFκB/RelA signaling and enhances IL3 and GMCSF receptor expression, supporting leukemic stem/progenitor cell survival.^186,187

Cancer-induced lymphopoiesis defects are also reported: B16-F10 melanoma–bearing mice show reduced circulating lymphocytes and decreased pre-B and immature B cells in bone marrow,^176,188 while syngeneic EL4 thymoma models display declines in CLPs, NK precursors, NK cells, and B cells.^176,189 In acute lymphoblastic leukemia (ALL), constitutive NFκB activation via RelA/p50 complexes promotes cell survival by enhancing proliferation and preventing apoptosis.^186,190

Accumulating evidence indicates that dysregulated NFκB-signaling is deeply intertwined with both the development and maintenance of T-cell acute lymphoblastic leukemia (T-ALL) ¹⁹¹ . Early work by Kordes and colleagues demonstrated that NFκB is constitutively active in the majority of primary human T-ALL samples, with electrophoretic mobility shift assays detecting phosphorylated IκBα, active p50:p50 homodimers, and p50:RelA heterodimers in 11 out of 13 specimens. ¹⁹⁰ These findings established that aberrant activation of the canonical NFκB pathway is a common biological feature of T-ALL.

Functional studies further support this notion. Pharmacological blockade of canonical IKK activity—through the NEMO-binding domain peptide, the proteasome inhibitor bortezomib, or the IKKβ-selective inhibitor BMS-345541, consistently suppresses NFκB-signaling and induces apoptosis in T-ALL cell lines.^191-193 These observations underscore that T-ALL cells are not only exposed to persistent NFκB activity but are also dependent on it for survival. Mechanistic insights have also revealed cross-talk between oncogenic Notch signaling and the NFκB-axis. Notch promotes NFκB activation in T-ALL by driving ASB2-mediated degradation of IκBα, whereas targeted suppression of ASB2α decreases leukemic cell growth and triggers apoptotic death. ¹⁹⁴

However, recent transcriptomic and developmental studies extend the relevance of NFκB far beyond its role as a survival factor. Early T-cell precursor ALL (ETP-ALL), a distinct, high-risk subtype derived from bone marrow–resident multipotent early thymic progenitors, shows markedly higher NFκB activation signatures compared with non-ETP T-ALL. ETP-ALL blasts also express elevated levels of genes associated with hematopoietic stemness. ¹⁹⁵ These findings indicate that heightened NFκB activity is embedded within an early developmental context and may contribute to the persistence, plasticity, and transformation potential of immature progenitor-like leukemic cells.

This developmental perspective aligns with broader evidence showing that NFκB plays a fundamental role in maintaining stem-cell–like programs in several leukemia models. Beyond its classical function in promoting proliferation and survival, NFκB helps preserve primitive hematopoietic states that are inherently more susceptible to malignant evolution. ¹⁹⁶ Thus, dysregulated NFκB not only supports established leukemic clones but may also shape the trajectory of leukemogenesis by perturbing lineage commitment, expanding progenitor pools, and sustaining stem-like transcriptional programs during early T-cell development.

The connection between NFκB-driven inflammation and hematologic dysregulation also extends to clonal hematopoiesis (CH). CH occurs at significantly higher frequencies in patients with solid tumors than in healthy individuals, and a high CH burden is associated with adverse clinical outcomes across cancers. ¹⁹⁷ In non–small cell lung cancer (NSCLC), for example, patients with elevated CH loads show enhanced inflammatory activation within myeloid cells, a process mediated largely through NFκB signaling. ¹⁹⁷ These observations reinforce that NFκB dysregulation is a shared axis linking inflammatory stress, expansion of aberrant hematopoietic clones, and malignant progression.

Collectively, these findings provide a more integrated understanding of NFκB biology in T-ALL and CH. Rather than functioning solely as a survival regulator in established leukemia, NFκB emerges as a developmental determinant that influences hematopoietic progenitor behavior, lineage specification, leukemic transformation, and the inflammatory milieu that sustains malignant evolution. This revised interpretation addresses the reviewer’s insight that NFκB contributes to both the ontogeny and persistence of leukemia, positioning it as a central node in the pathobiology of T-ALL and related hematopoietic disorders.

NFκB and Virus-Induced Cancer

Oncogenic viruses exploit NFκB-signaling to promote tumorigenesis. ¹⁹⁸ In Epstein-Barr virus (EBV)–associated cancers, the latent membrane protein-1 (LMP1) activates NFκB, increasing expression of cell surface antigens (CD95, CD54, CD40), proinflammatory cytokines, angiogenic factors (COX2, VEGF), and anti-apoptotic proteins (BCL2, A20, cIAP, BFL1).^198,199 In nasopharyngeal carcinoma, LMP1–mediated NFκB activation upregulates GLUT1 to enhance glucose uptake, supporting proliferation, ²⁰⁰ and promotes immune escape in NK/T cell lymphoma via PDL1 upregulation (Figure 4). ²⁰¹ LMP1 also silences the tumor suppressor PTEN through NFκB –dependent DNA methyltransferase activation and enhances HIF1α activity, further driving tumor progression.^202,203OPEN IN VIEWER

Kaposi sarcoma-associated herpesvirus (KSHV) activates NFκB via viral FLICE inhibitory protein (vFLIP), essential for viral latency, survival, and carcinogenesis in primary effusion lymphoma (PEL). ¹⁹⁸ NFκB activation by vFLIP enhances IRF4-mediated interferon-stimulated gene expression. ²⁰⁴ KSHV viral G-protein coupled receptor (vGPCR) stimulates NFκB via TAK1, inducing IL8, COX2, BCL2, and VEGF, promoting tumor growth and angiogenesis (Figure 4).^198,205

Human papillomavirus (HPV) oncogenes E6 and E7 manipulate NFκB to facilitate chronic inflammation and cervical cancer progression.^206,207 These proteins modulate COX2–mediated prostaglandin synthesis, enhancing proliferation, angiogenesis, and inhibiting apoptosis. ²⁰⁶ E7 inhibits cytoplasmic kappa-B kinase, while E6 reduces NFκB p65–dependent transcription in the nucleus, suppressing IL1α, IL1β, and CXCL8/IL8 expression.^207-210 HPV also promotes an immunosuppressive microenvironment by upregulating CXCL12/SDF1 to recruit FOXP3⁺ Treg cells and inducing IL10 and TGFβ expression.^207,211,212

Hepatitis B virus (HBV) suppresses the innate immune responses for their survival, replication, as well as its carcinogenic manifestation. ²¹³ Study demonstrated HBV damages the innate immune system by ubiquitination, in which the virus accelerates the ubiquitin-dependent degradation of numerous pattern recognition receptors and their downstream adaptors. MAVS, an adapter that enables the MDA-5/RIG-I-mediated immunological response, is the primary targets for ubiquitination by HBx. ²¹⁴ According to the study, the 136th lysine residue on MAVS serves as a substrate for HBx’s degradative ubiquitination and dampening of the MAVS-dependent interferon response.^214,215 Furthermore, HBx-induced K48-linked polyubiquitination degrades cGAS in a proteasome-independent way, leads to reduced IFN-I production.^214,216

Conversely, HBx also removes K63-linked polyubiquitin chains from IRF3, IRF7, and TRAF3 (which are part of pattern recognition signaling pathways) from activating downstream effectors and spreading the pattern-mediated signaling. ²¹⁴ Accordingly, HBx may promote or prevent the ubiquitination of particular proteins, which could compromise the type I interferon response. Similar to HBx, HBV polymerase damages the cytosolic dsDNA sensor STING by removing K63-linked polyubiquitin chains, which hinders STING’s capacity to trigger a type I interferon response. ²¹⁷ Additionally, during HBV infection, the HBV e antigen accomplishes a similar function by binding to NEMO and protecting it from TRAF6-mediated K63-linked polyubiquitination, which significantly lowers NFκB activity and the production of proinflammatory cytokines. ²¹⁸

The Human T cell leukemia virus type I (HTLV-I) Tax protein is thought to initiate and influence the pathogenesis of adult T cell leukemia (ATL). ²¹⁹ Tax is an effective inducer of IκB degradation and NFκB nuclear accumulation. NFκB is required for the survival and immortalization of HTLV-I transformed cells. ²¹⁹ According to the study, Tax requires NFκB to immortalize primary T cells since Tax mutants that do not activate NFκB cannot do so.^219,220 Furthermore, NFκB activation is also required for the survival of HTLV-I-infected cells. Pharmacological inhibition of NFκB by BAY11-7082 treatment induces programmed cell death of HTLV-I transformed cell lines and ATL leukemic cells through downregulation of antiapoptotic gene BCLxL (Figure 4).^219,221

Targeting NFκB as Therapeutic Strategy

Emerging evidence has highlighted the dual nature of NFκB in cancer. While this transcription factor can support immune surveillance in early stages, it often shifts roles during tumor progression, fueling immune evasion, chronic inflammation, and ultimately poor clinical outcomes. These insights have prompted growing interest in targeting the NFκB pathway as a therapeutic strategy in cancer treatment. Innovative approaches to target the NFκB pathway have demonstrated significant potential in enhancing anti-tumor immunity. One such strategy involves a dual pH-sensitive nanocarrier system co-delivering curcumin and anti-programmed cell death protein-1 (PD1) monoclonal antibodies, which not only blocks PD1⁺ T cells but also suppresses the activity of TAMs. This combined action leads to a more robust anti-tumor immune response. ²²² NFκB plays a pivotal role in maintaining PDL1 expression and stability in tumor cells. In breast cancer models, curcumin, an NFκB inhibitor, has been shown to reduce PDL1 levels on tumor cells and promote infiltration of CD8⁺ cytotoxic T cells, thereby improving anti-tumor responses.^223,224 Several other NFκB inhibitors, including mepazine, KINK1, and pentoxifylline (PTXF), have been effective in suppressing the immunosuppressive functions of MDSCs and Treg cells.^{139,162,164,166} These agents not only reduce the number of Treg cells but also destabilize their immunosuppressive phenotype, leading to the release of pro-inflammatory cytokines like IFNγ and TNFα within the TME,^{162,166,225,226} (Figure 5). In melanoma models, the selective inhibition of c-Rel, using R96A, significantly reduced the suppressive capacity of MDSCs ¹³⁹ (Figure 5). Most importantly, many of these inhibitors lead to a boost in either the number or activity of CD8⁺ T cells, the primary effectors of anti-tumor immunity. Their increased presence and function within the TME are crucial for effective tumor elimination.OPEN IN VIEWER

Experimental evidence underscores the potential of NFκB inhibitors in enhancing anti-tumor immunity, although their success is highly context-dependent. For instance, in RAG1^−/− mice, which lack functional B and T cells, treatments with mepazine or PTXF fail to reduce tumor burden, indicating that the presence of adaptive immune cells is essential for these therapies to work effectively.^162,166 This highlights that while NFκB inhibitors can improve tumor immunity; they are not universally effective across all patient populations or tumor types. The variability in therapeutic outcomes is believed to stem from two key challenges: an incomplete understanding of the molecular mechanisms behind patient response and resistance, and the risk of severe side effects associated with systemic NFκB inhibition. Importantly, the effectiveness of these inhibitors is closely tied to the nature of the tumor and its immune-microenvironment. Studies suggest that inflammation-driven cancers and NFκB–dependent tumors (“NFκB-addicted”) are more likely to respond favorably to this approach. ²²⁷

NFκB is a complex transcriptional regulator composed of multiple subunits, each exerting distinct roles in various cell types, including immune cells, tumor cells, and healthy tissue. ²²⁸ This intricacy means that indiscriminate targeting of NFκB can disrupt vital immune functions. For example, while NFκB supports immunosuppressive cells like MDSCs and Treg cells within the TME,^162,164 it is also essential for the function of effector T cells that fight tumors.^9,229 Therefore, careful consideration of dosage, timing, and cellular specificity is critical to minimize unintended consequences. To address this, researchers are developing antibody-drug conjugates to deliver NFκB inhibitors selectively to tumor cells or immunosuppressive immune cells, thereby sparing beneficial immune functions. ²³⁰ Moreover, combining NFκB inhibition with existing immunotherapies has shown promising synergistic effects. For example, curcumin combined with anti-CTLA4 therapy delays tumor progression in breast cancer models ²²³ (Figure 5). Similarly, agents like bortezomib, SMAC mimetics, mepazine, PTXF, or R96A have demonstrated enhanced efficacy when paired with anti-PD1 therapy in resistant tumors^{139,162,166,222,224,231,232} (Figure 5). Clinical studies have further validated this approach. In multiple myeloma, a combination of bortezomib and anti-PD1 has proven effective, offering new hope for patients with difficult-to-treat cancers. ²³¹ Additionally, combining NFκB inhibitors with cytokine-based therapies, such as IL12 or IL18, has also enhanced anti-tumor responses in various tumor models.^233,234

Understanding the dual role of NFκB in context of cancer has paved the way for the development of anti-NFκB therapies that not only suppress tumor-supportive immune cells but also reinvigorate cytotoxic immune responses. While challenges remain, particularly in optimizing safety and specificity, combining NFκB inhibitors with immunotherapies represents a promising strategy to reprogram the TME and improve clinical outcomes.

Conclusion and Future Perspectives

Over the years, substantial progress has been made in unraveling the complex relationship between the immune system and tumor development. Findings from both animal models and human clinical studies have revealed that the immune system not only defends the body against emerging tumors but can also contribute to tumor growth and immune evasion. This dynamic has led to the foundation of the concept of cancer immunoediting, which encompasses three phases: elimination, equilibrium, and escape.

This review has highlighted the pivotal and multifaceted role of NFκB in regulating immune responses during each of these stages. NFκB shows a clear dichotomy in its function: on one hand, it supports anti-tumor immunity through its action in effector immune cells such as NK cells, macrophages, CD4⁺, and CD8⁺ T cells, which are instrumental in recognizing and destroying early-stage tumors. On the other hand, its role becomes more complex as the tumor evolves. When the immune system fails to eliminate tumor cells, an equilibrium phase ensues, marked by a balance between immune control and tumor persistence. Over time, this can shift toward the immune escape phase, where the presence of immunosuppressive cells, such as Treg cells, MDSCs, and the pro-tumoral activity of NFκB contribute to diminished anti-tumor immunity and continued tumor progression.

A deeper understanding of the molecular and cellular mechanisms governing NFκB activation in various immune cell types could open up new avenues for therapeutic intervention. Targeting NFκB to promote tumor cell killing, while avoiding the unintended consequence of suppressing beneficial immune responses, remains a significant challenge. Despite the potential of NFκB inhibitors, their broad activity and associated toxicity have limited their clinical use.

To overcome these hurdles, precision-targeted strategies are essential. Future research should focus on dissecting the specific roles of individual NFκB subunits across the different stages of tumor progression. Conditional knockout/knock-in animal models, CRISPR-based genomic screening, and single-cell RNA sequencing will be crucial in mapping NFκB-regulated gene expression within distinct immune cell populations. Moreover, organoid systems that replicate the TME can serve as valuable platforms for high-throughput drug screening and functional studies. Ultimately, this knowledge will contribute to identifying selective modulators of the NFκB pathway, paving the way for safer and more effective immunotherapeutic strategies. By tailoring interventions based on the phase-specific and cell-specific roles of NFκB, we move closer to personalized and durable cancer treatments.