TNFR1 is a type I transmembrane receptor with four cysteine-rich domains (CRD1-CRD4): CRD1 stabilizes pre-assembly, CRD2-CRD3 contains the TNF interface, and CRD4 positions binding near the membrane to couple with intracellular death domain signaling. This signals NF-κB-mediated survival, caspase-8-mediated apoptosis, or RIPK1 RIPK3, and mixed lineage kinase domain-like protein (MLKL)-mediated studies (He et al., 2021[24], Rivas et al., 2008[53]) show that pre-assembled TNFR1 arrays enhance responsiveness by reducing the energetic costs of trimer interactions. The ligand form is a key determinant: membrane-bound TNF (tmTNF) forms high-affinity interactions that maintain multivalent TNFR1 interactions, whereas soluble TNF (sTNF) promotes transient interactions. El Yazidi-Belkoura et al. showed that tomatoes have longer receptor residency (El Yazidi-Belkoura et al., 2003[16]), and Branschädel et al. correlated signal strength with ligand concentration and receptor pre-assembly (Branschädel et al., 2010[5]). This aligns with receptor-proximal findings: stabilized ubiquitin-rich Complex I enables NF-kB-dependent survival; reduced ubiquitin scaffolds or restricted caspase-8 leads to cytosolic Complex II variants causing apoptosis or, with RIPK1 kinase, necrosome assembly, and necrosis (Cruceriu et al., 2024[10], Xu et al., 2006[69]).

These ligand effects are modulated by the cell surface, resolving model discrepancies. CRD2-CRD3 accessibility and trimer formation are modulated by N-glycosylation and receptor density. Division into cholesterol-/sphingolipid-rich microdomains facilitates TNFR1 and adaptor protein aggregation to enhance Complex I in pro-survival environments or promote death signaling when checkpoints are dysfunctional. Soluble TNFR1 from proteolytic shedding buffers local TNF and reconfigures gradients, whereas TNFR2 crosstalk modulates ligand and adaptor availability. Studies have linked CRD-directed receptor sorting and ligand shape to fate selection in breast cancer.

These membrane logics are connected to epigenetic states: NF-kB occupancy by Complex I supports chromatin-modifying enzymes and pro-survival states, while scaffold collapse with defective caspase-8 enables necroptosis through chromatin reprogramming. TNFR1 fate and downstream epigenetic effects are programmed by structural determinants, ligand form, and membrane (Cruceriu et al., 2024[10]). Future studies should quantify fMnTNF versus sTNF interactions and Complex I residency in physiological membranes. Combining receptor biophysics with adaptor ubiquitin architecture and chromatin profiling will enable the rational selection of combinations directing TNFR1 to therapeutic death programs.

Receptor-proximal checkpoints regulate TNFR1 signaling to determine whether NF-κB-mediated cell survival will persist or switch to apoptosis or necroptosis. After ligation, a membrane-bound Complex I forms around TNFR1, including TRADD, RIPK1, TRAF2/5, cIAP1/2, and LUBAC, stabilized by the TAB/TAK1 and IKK complexes to maintain survival transcription. This survival bias aligns with clinical results: higher TNF-alpha correlates with higher stage and worse prognosis (Hu et al., 2024[26]), and TNFR1 deficiency reduces tumor growth and metastasis (Yang et al., 2017[70]). With maintained ubiquitin platforms and TAK1/IKK signaling, pro-survival transcription occurs, and caspase activation is inhibited (He et al., 2021[24]).

Deubiquitinases or cIAPs depletion destabilizes Complex I, enabling cytosolic death-inducing assemblies. When caspase-8 is balanced with cFLIP-L, apoptosis occurs through BID activation and mitochondrial permeabilization (Xu, 2006[69]). With defective caspase-8 activity or TAK1/IKK, RIPK1 kinase interacts with RIPK3 and MLKL for necroptosis, supported by evidence that necrostatin-1 suppresses cell death and TNF stimulates MLKL phosphorylation (Lin et al., 2004[40], Zhang et al., 2018[79]). High RIPK1/RIPK3/MLKL levels correlate with decreased viability, necessitating necroptotic axis profiling (Liu et al., 2016[41]). Membrane-anchored TNF is demonstrably more effective in promoting high-avidity clustering, which is a crucial element for successful cellular interactions. In contrast, sTNF leads to shorter and less consequential interactions. This distinction highlights the essential role of membrane-anchored TNF in augmenting cellular communication and functions (Branschädel et al., 2010[5]). Signal strength is related to ligand concentration and TNFR1 pre-assembly (Branschädel et al., 2010[5]). Cholesterol-rich microdomains enhance Complex I survival, whereas weak scaffolds favor death complexes (He et al., 2021[24], Rivas et al., 2008[53]). TNFR2 inhibition restrains cell proliferation and, when combined with PD-L1 inhibition, increases CD8+ T cell (Fu et al., 2021[19]). Under certain conditions, TRAIL co-engagement with tmTNF can increase chemoresistance (Xu et al., 2006[69], Yoon et al., 2016[75]).

NF-κB activation mediated by TRADD stimulates growth and can be negated by TRADD knockdown, consistent with survival in Complex I stabilization (Cai et al., 2017[6]). Heregulin suppresses TNFR1NF-κB and prepares cells for apoptosis, providing an advantage for cell death (Moatti and Cohen, 2021[46], Sprowl et al., 2012[60]). These data suggest that equivalent TNF exposure has different effects in breast cancer: ubiquitin architecture, caspase-8/cFLIP balance, kinase competency for RIPK1 necroptosis, ligand form, and receptor microdomain residency combine to favor survival, apoptosis, or necroptosis.

These proximity receptor decisions create epigenetic fate-reinforcing decisions. Stabilized Complex I maintains NF-Kb occupancy at enhancers and promoters, recruiting histone acetyltransferases, SWI SNF remodelers, and methyltransferases to establish pro-survival chromatin. Complex II or necrosome formation coincides with the redistribution of DNA/histone enzymes and reprogramming of non-coding RNA and metabolic cofactors, enabling efficient apoptosis or necroptosis. Future efforts should combine ubiquitin-scaffold integrity and RIPK1 activity readouts with chromatin profiling to identify predictive biomarkers. Modulating TNFR1 gating through rational combinations while monitoring the epigenetic state will guide results towards therapeutic cell death with reduced pro-tumor inflammation.

Necroptotic execution downstream of TNFR1 occurs when pro-survival scaffolds degrade and caspase-8 is inhibited, allowing RIPK1 to form a necrosome with RIPK3, which phosphorylates MLKL. Phosphorylated MLKL oligomers disrupt membrane integrity, leading to cell death and DAMP release. This process depends on adaptor loading, caspase competence, ligand formation, and membrane organization. High RIPK1 levels correlate with enhanced necroptosis, TNF pathway upregulation, and poor survival (Yoon et al., 2016[75]). RIPK3 knockdown reduces MLKL phosphorylation, necroptotic death, HMGB1/ATP release, and CD8⁺ T cell infiltration, whereas MLKL activation promotes dendritic cell maturation (Yang et al., 2016[71]). Phosphorylated MLKL rapidly translocates to the nucleus, and blocking nuclear import reduces necroptosis (Snyder et al., 2019[59], Yoon et al., 2016[75]). In triple-negative models, AQP1 silencing reduces growth, whereas RIPK1 knockdown rescues proliferation (Hou et al., 2019[25]). RIPK1/RIPK3 activation increases CD8⁺ cells and IFN-γ, reduces tumors, and improves survival, especially with PD-1 blockade (Wang et al., 2024[65]). RIPK1 inhibitors suppress necroptosis and improve survival (Cai et al., 2017[6]). A seven-gene necroptosis classifier was used to stratify risk and PD-L1 levels (Liu et al., 2016[41]). These studies show how receptor-proximal events lead to necrosome formation, demonstrate context-dependent immunogenic effects, and support strategies using RIPK1 inhibition or checkpoint-partnered necroptosis induction.

The downstream fate of TNFR1 depends on the inflammatory tone, receptor-proximal complex assembly, and caspase/RIP checkpoints. TNF-α establishes a pro-survival baseline by enhancing NF-κB activity, proliferation, and in vivo growth, positioning inflammation as a driver of tumor fitness (Zou et al., 2020[82]). Increased TRADD recruitment enhances NF-κB and suppresses apoptosis, whereas reducing TRADD restores caspase-3 activity (Cai et al., 2017[6]). TNFR1 activation increases proliferation, whereas its silencing enhances caspase-3 and tumor apoptosis, indicating that the balance between Complex I signaling and death-complex formation is modifiable (Xu et al., 2006[69]). When caspase-8 is restrained and RIPK1 is competent, signaling shifts to regulated necrosis. In breast cancer, RIPK1/RIPK3 upregulation and MLKL activation are correlated with reduced viability and poor prognosis (Moatti and Cohen, 2021[46], Sprowl et al., 2012[60]). TNF-α plus TRAIL increases apoptosis, enhances doxorubicin cytotoxicity, and raises caspase-8 levels (Liu et al., 2016[41]). Additionally, heregulin suppresses TNFR1-NF-κB signaling and increases TNF-α-induced apoptosis (Moatti and Cohen, 2021[46], Sprowl et al., 2012[60]). These studies show that inflammatory inputs bias towards survival, while rational combinations can tip the balance towards antitumor death (Figure 3(Fig. 3); Table 1(Tab. 1); References in Table 1: Bai et al., 2024[3]; Bilecova-Rabajdova et al., 2014[4]; Cai et al., 2017[6]; Chinnaiyan et al., 2000[8]; Chun et al., 2021[9]; Davey et al., 2021[12]; El Yazidi-Belkoura et al., 2003[16]; Eteshola et al., 2021[17]; Fu et al., 2018[18]; Fu et al., 2021[19]; Guo and Yuan, 2020[21]; He et al., 2021[24]; Hou et al., 2019[25]; Hussain et al., 2017[27]; Katanov et al., 2015[29]; Ke et al., 2023[30]; Khalili-Tanha and Moghbeli, 2021[31]; Kochumon et al., 2021[34]; Lafont et al., 2017[37]; Li et al., 2020[39]; Li et al., 2023[38]; Lin et al., 2004[40]; Moatti and Cohen, 2021[46]; Moerke et al., 2019[47]; Montinaro et al., 2022[48]; Nicolè et al., 2022[50]; Peterson et al., 2017[51]; Scarpellini et al., 2023[56]; Sprowl et al., 2012[60]; Van Berckelaer et al., 2024[62]; Vanden Berghe et al., 2016[63]; Wang et al., 2024[65]; West, 2019[66]; Wu and Zhou, 2010[68]; Xu et al., 2006[69]; Yang et al., 2016[71]; Yao et al., 2025[72]; Yin et al., 2021[74]; Yoon et al., 2016[75]; Yu et al., 2022[76]; Zhang et al., 2018[79]; Zhang et al., 2022[78]; Zheng et al., 2025[81]).

The impact of TNFR1 signals is shaped by external cytokines, chemokines, and stromal signals, which guide breast cancer cells towards either survival or programmed cell death (PCD). TNF-α can promote survival in the tumor epithelium. Cai et al. demonstrated that exposure leads to increased proliferation and invasion, along with a notable rise in antiapoptotic mechanisms such as Bcl-2 and cyclin D1, while significantly reducing apoptotic commitment. This epithelial tendency is further reinforced by the transcriptional regulation of the inflammatory environment (Cai et al., 2017[6]). Meškytė et al. found that inhibiting ETV7 transcription triggers the expression of IL-6 and TNF-A, and that ETV7 inhibition reduced these cytokines, indicating that tumor-intrinsic programs might enhance or diminish the ligands that bind to TNFR1 (Meškytė et al., 2023[44]).

The microenvironment enhances these epithelial signals. Katanov et al. (2015[29]) found that after cancer development, fibroblasts release IL-6, IL-8, and CCL2, and this stromal secretion aids in the growth and migration of tumor cells, which is linked to the increased activity of fibroblasts(Katanov et al., 2015[29]). At the receptor level, He et al. observed that tumors exhibit increased TNFR1 expression compared to the corresponding normal tissue, along with elevated NF-kB activity, which leads to greater proliferative behavior. This places receptor density and transcriptional output on a shared axis that supports survival signaling in the presence of cytokines (He et al., 2021[24]). Downstream pathways present a clinical risk at a later stage. Elevated levels of RIPK1, RIPK3, and MLKL are associated with a higher likelihood of recurrence and extensive overexpression of the necroptotic machinery in tumors (Liu et al., 2016[41]). This suggests that even when upstream signals favor survival, inflammatory death mechanisms are ready and can be triggered if checkpoints fail. This scenario can be altered by counter-regulatory growth factors. Heregulin suppresses TNFR1/NF-KB signaling, activates caspase-3, reduces viability in the presence of TNF-α, and shifts the outcome towards apoptosis. Consequently, Zou demonstrated that the shift towards apoptosis can be pharmacologically influenced by a receptor-proximal survival bias (Zou et al., 2020[82]). In studies of diseases influenced by survival bias, it is crucial to incorporate cytokine profiles, stromal signatures, and TNFR1 levels for effective patient stratification. The development of therapeutic interventions should focus on targeting the inflammatory feedback loop induced by cancer-associated fibroblasts (CAFs) and the effectors RIPK1/3MLKL, with the aim of mitigating proliferative signaling and necro-inflammatory remodeling. HRG-like modulators that regulate TNFR1/NF-kB and restore caspase-dependent execution should be considered as sensitizers in biomarker-guided combination therapies.

Intracellular adaptors like TRADD and FADD, inhibitory nodes from TNFR2, and post-translational modifications including RIPK1 ubiquitylation and RIPK1/MLKL phosphorylation determine whether TNFR1 signaling promotes survival, apoptosis, or necrosis. Ubiquitin editing stabilizes Complex I, whereas caspase-8 enables necroptosis transition. TNFR2 interacts with this network by competing with the ligand and adaptor pools and modifying the residency threshold of Complex I. In breast tumors, TNFR2 levels are elevated compared to those in normal tissue, which is associated with increased NF-KB production and promotes growth; its inhibition reduces these signals, while TNFR1 is associated with an apoptotic phenotype (He et al., 2021[24]). When tumor cells are exposed to TNF-alpha, the survival pathway is enhanced by boosting NF-kB targets and pro-growth cytokines, leading to accelerated in vivo expansion, indicating that receptor-proximal bias is prioritized over transcriptional reinforcement (Cai et al., 2017[6]). The concept of natural-product modulation emphasizes the same gatekeeping principle: Erioctyol reduces TNFR1 levels, decreases TRADD/FADD recruitment, suppresses NF-kB, and restores caspase-3 activity, thereby steering the outcome towards apoptosis in the presence of TNF-α (Debnath et al., 2022[13]).

Transcriptional programs also play a role in influence this pathway. When ETV7 is inhibited, it triggers the activation of interferon-stimulated genes, reduces STAT1 activation, and accelerates tumor growth. This suggests that the breakdown of an antiviral-like tone does not limit the growth of tumors responsive to TNF-alpha (Meškytė et al., 2023[44]). Microenvironmental cytokines contribute to this effect; cancer-associated fibroblasts secrete IL-1 2-linked chemokines and interleukins, which enhance proliferation and motility, effects that are mitigated when NF-kB is inhibited (Katanov et al., 2015[29]). High levels of RIPK1, RIPK3, and activated MLKL are associated with more severe disease. Inhibition of RIPK1/3 via genetic or pharmacological means can halt cell proliferation, metastasis, and tumor progression. Consequently, the necroptotic module serves as a valuable target for treatment and prognosis (Liu et al., 2016[41]). Counter-regulatory growth mechanisms have the potential to counteract these survival signals. Heregulin inhibits TNFR1/NF-KB, activates caspase-3, reduces cell viability, and diminishes tumor size in TNF-a environments. This indicates its capability to reverse survival signals by utilizing natural contextual cues (Zou et al., 2020[82]). System-level analyses have cautioned that alterations in the TNF axis can influence drug exposure and tumor cell apoptosis. This suggests that drug behavior and pathway regulation are interconnected and require careful equilibrium (Sprowl et al., 2012[60]).

To mitigate deleterious inflammation without disrupting the TNFR2-adaptor interaction, it is advisable to target TNFR2 by modifying its survival structure. This approach should be complemented by the regulation of the RIPK1/RIPK3-MLKL pathway to curtail harmful inflammation. Monitoring drug concentrations is crucial for ensuring a consistent and beneficial therapeutic response. This can be accomplished by preparing the axis for the TNF-adaptor interaction and maintaining therapeutic levels.

DAMPs released from stressed or dying breast cancer cells enhance inflammation and influence immune cell trafficking, whereas cytokines modulate whether this environment inhibits or promotes disease progression. TNFR1 integrates DAMP signals with NF-κB/STAT outputs to influence cell survival or death. TNF-α initiates a pro-tumor program in breast cancer cells, increasing proliferation and IL-6/IL-8 and VEGF production in these cells. TNFR1 blockade reverses over half of these effects, establishing it as an inflammatory driver (Cai et al., 2017[6]). In inflammatory breast cancer, XIAP overexpression compared to non-inflammatory breast cancer is associated with elevated TNF-α/IL-6 levels and poorer survival, linking apoptosis resistance to an aggressive phenotype (Van Berckelaer et al., 2024[62]). A TNFR1-targeted 18F PET probe showed higher uptake in inflamed tissue than in controls, with reduced signal by blocking, supporting non-invasive quantification of inflammation and patient monitoring (Fu et al., 2018[18]). Tumor-derived DAMPs activate myeloid cells, increasing macrophage TNF-α and IL-6 levels and CD86⁺ fractions; this activation enhances tumor cell proliferation and migration, evidencing a DAMP-macrophage loop that perpetuates necro-inflammation (Eteshola et al., 2021[17]). These studies outline a sequence from cytokine amplification through antiapoptotic buffering to measurable pathway activity and immune remodeling. Three strategies have emerged: combining TNFR1 antagonism with DAMP signaling mitigation, using TNFR1 PET for patient monitoring, and disrupting macrophage reinforcement to transform necro-inflammation into productive immune control. These findings address how DAMP biology and TNFR1 signaling influence the immune context of breast cancer.

Tumor-stroma interactions regulate the necro-inflammatory environment through cytokines from mesenchymal and immune cells via tumor-intrinsic pathways, with TNFR1 playing a central role. Katanov et al. showed that mesenchymal stromal cells increased IL-6 by 2.5-fold and TNF-α by 1.8-fold, decreased IFN-γ by 40 %, induced M2-like macrophages, and accelerated xenograft growth, creating an immunosuppressive niche (Katanov et al., 2015[29]). Cai et al. demonstrated that TNF-α enhanced tumor fitness, increasing viability by 40 %, reducing apoptosis by 25 %, accelerating wound closure, and elevating NF-κB and cyclin D1 levels, linking stromal cytokines to tumor cell proliferation (Cai et al., 2017[6]). Van Berckelaer et al. (2024[62]) found that XIAP overexpression was observed in 76 % of inflammatory breast cancers versus 42 % of non-inflammatory cases, with reduced survival and increased NF-κB activity (Cai et al., 2017[6]). Debnath et al. showed that eriodictyol reduced TRADD/FADD complex formation, decreased NF-κB activity, reduced TNF-α/IL-6 levels, increased apoptosis, and improved survival (Debnath et al., 2022[13]). These studies progressed from stromal effects to tumor response and targeted TNFR1 disruption. Future priorities include patient stratification based on cytokine signatures and the development of anti-inflammatory modulators for tumor control.

Necroinflammation associated with TNFR1, when combined with the activation of endothelial cells and matrix remodeling, promotes angiogenesis, invasion, and metastasis, thereby facilitating tumor growth. Sprowl et al. identified that in docetaxel-resistant MCF-7TXT9/10 cells, chemotherapy induced a self-sustaining TNF/NF-κB loop, characterized by increased TNF-alpha production and enhanced NF-kappaB DNA binding. However, this loop can be interrupted by selectively inhibiting TNFR2, which restores the sensitivity of the cells to chemotherapy (Sprowl et al., 2012[60]). Furthermore, Bilecova-Rabajdova et al. observed an upregulation of endothelial DR6 expression at both the transcript and protein levels, which was associated with Ki-67, consistent with pro-angiogenic remodeling of blood vessels (Bilecova-Rabajdova et al., 2014[4]).

Cai et al. (2017[6]) identified that TNF-alpha promotes a pro-metastatic phenotype by upregulating NF-KB and cyclin D1, which enhances cell proliferation, xenograft growth, and microvessel density, which are linked to neovascularization and invasive growth (Cai et al., 2017[6]). He et al. (2021[24]) revealed that TNFR1 activation leads to apoptosis, whereas TNFR2 promotes cell proliferation. Manipulating these pathways can decrease TNF-alpha/IL-6 levels in the tumor microenvironment, thereby inhibiting angiogenesis and tumor invasion (He et al., 2021[24]). Van Berckelaer et al. (2024[62]) discovered that inflammatory breast cancers with high XIAP levels contain CD163 3 tumor-associated macrophages and PD-L1, suggesting niches that support metastasis (Van Berckelaer et al., 2024[62]). Collectively, TNF/NF-KB loops triggered by chemotherapy, endothelial activation and remodeling, inflammation-driven invasion and metastasis, receptor-level bias and cytokine regulation, and immune-suppressive niches demonstrate a connection between necroinflammation and angiogenesis. This supports three strategies: disrupting TNF/TNFR2 feedback during taxane therapy to reduce invasion, integrating vascular-targeted therapies with cytotoxic regimens for DR6-dependent proliferation markers, and preventing TNF/TNFR2 interaction while promoting TNFR1-mediated therapeutic cell death to break pro-angiogenic circuits.

Inflammatory signaling mediated by TNFR1, which exhibits resistance to therapeutic interventions, promotes cellular survival under cytotoxic stress and maintains residual clones that may contribute to disease recurrence. This condition is sustained by the activation of NF-kB, antiapoptotic mechanisms and cytokine feedback loops. Sprowl et al. demonstrated in breast cancer models treated with taxanes that docetaxel induced TNF-α, and resistant MCF-7TXT9/10 cells exhibited increased TNF-α production with heightened NF-kB binding. Inhibition of TNF-2 restored drug sensitivity, whereas suppression of NF-kB enhanced the effect of docetaxel (Sprowl et al., 2012[60]). This establishes a chemotherapy→TNF→NF-KB loop that stabilizes the survival mechanisms during treatment. Cai et al. found that TNF-alpha promotes breast cancer cell growth, increases tumor burden, and prevents apoptosis through NF-KB targets (Cai et al., 2017[6]). Zhang et al. demonstrated that transmembrane TNF-α confers resistance to doxorubicin by inhibiting caspase-3 and increasing Bcl-2 levels, whereas neutralizing membrane TNF reverses these effects (Zhang et al., 2018[79]). Clinically, He et al. discovered that TNFR1 positivity is associated with higher grade and longer progression-free survival, whereas TNFR2 positivity is correlated with nodal metastasis (He et al., 2021[24]). Van Berckelaer et al. found that tumors with elevated XIAP levels exhibit more nodal involvement and shorter disease-free intervals than those with low XIAP (Van Berckelaer et al., 2024[62]). Zou et al. showed that heregulin reprograms TNFR1 to support survival by reducing apoptosis and increasing Bcl-2 (Zou et al., 2020[82]). These studies indicate that chemotherapy activates TNF signaling, enhancing survival programs; the receptor context influences drug tolerance, while receptor profiles predict progression risk; and growth factors can switch TNFR1 to a survival mode. Therapeutic strategies may include the use of TNF/TNFR2 inhibitors during taxane treatment, combination of NF-kB regulation with cytotoxic drugs, and profiling of TNFR1/TNF2/XIAP to identify high-risk patients.

Strategies aimed at targeting necroptosis, encompassing both small-molecule and biologic approaches, are designed to mitigate the effects of TNFR1-mediated cell death and its subsequent effects on angiogenesis, invasion, and immune modulation. These strategies operate by either inhibiting the TNF-alpha/TNFR1 pathway or disrupting the RIPK1-RIPK3-MLKL signaling cascade, thereby limiting vascular adaptability and preventing tumor recurrence. This approach is based on the tumor burden along this pathway. Nicolè et al. (2022[50]) identified a significant increase in RIPK1, RIPK3, and MLKL in aggressive diseases; elevated RIPK3 levels were associated with reduced five-year survival rates; MLKL expression was prevalent in triple-negative tumors; and silencing RIPK1 reduced invasion, highlighting this axis as a potential therapeutic target (Nicolè et al., 2022[50]). Building on this pathological evidence, Liu et al. (2016[41]) observed that necroptotic activity was linked to tumor growth and new blood vessel formation, with increased levels of p-MLKL and RIPK1/3/necroptotic activity, along with higher microvessel density and tumor burden, reinforcing the case for pathway inhibition in the presence of the necroptotic program (Liu et al., 2016[41]).

The endothelium plays a pivotal role in understanding the vascular dynamics. Hänggi et al. (2017[23]) demonstrated that enforced RIPK3 resulted in the destabilization of endothelial barriers across various experimental conditions, whereas inhibiting RIPK1 reduced leakage, and the absence of RIPK3 impeded metastatic spread. This indicates that targeting RIPK1 may prevent both dissemination and intratumoral necroinflammation. This mechanism is associated with ligand-receptor interactions. TNF-alpha promotes growth, activates NF-KB, encourages invasion, and inhibits apoptosis in breast cancer models (Hänggi et al., 2017[23]). However, Cai et al. (2017[6]) disrupted this process, showing that blocking TNF-alpha signaling in response to cytokine overload suppressed proliferation and prevented apoptosis (Cai et al., 2017[6]).

These elements represent interventional data on vascular plasticity that inform treatment strategies. According to Li et al. (2023[38]), RIPK1 activation enhances vasculogenic mimicry, whereas RIPK1 inhibition reduces this characteristic. Tumors exhibiting increased necroptosis also demonstrate denser microvasculature and decreased survival rates (Li et al., 2023[38]). By integrating Nicolè's biomarker data with Liu's insights on growth and angiogenesis, Hänggi's findings on barriers and metastasis, and Cai's cytokine-driven survival program, a coherent strategy emerges: employing RIPK1 prophylaxis and TNF-axis blockade in biomarker-enhanced diseases, using it alone or in conjunction with cytotoxic or immune agents, to reduce permeability, limit vasculogenic mimicry, and slow disease progression in accordance with necroptotic pathways.

Innovative strategies that integrate the regulation of necroptosis with cellular therapies aim to transform TNFR1-mediated cell death into sustained control and limit cell evasion through inflammation. This can theoretically be achieved by combining the effects of TRAIL agonism, chemotherapy, radiotherapy, or checkpoint inhibition with a modulator of the RIPK1 RIPK3/MLKL axis or TNF/TNFR signatures, ensuring a unified outcome for the cells. Foundational evidence for this concept was provided by Chinnaiyan et al. (2000[8]), who demonstrated that combining doxorubicin or paclitaxel with TRAIL resulted in significant apoptosis, characterized by notable caspase-8 activation and cytochrome c release, rather than minimal apoptosis (Chinnaiyan et al., 2000[8]). Addressing the issue of which patients might benefit from such intensified treatment, Nicolè et al. (2022[50]) identified tumors with elevated RIPK1/3/MLKL levels and poorer prognoses, supporting the use of biomarkers to guide the addition of pathway-targeted agents to standard care rather than applying them indiscriminately (Nicolè et al., 2022[50]).

Building on the research conducted by Liu et al. (2016[41]), mechanistic reinforcement has demonstrated that CRISPR-mediated loss of RIPK1/3/MLKL effectively suppresses anchorage-independent growth and the establishment of xenografts. Furthermore, necrostatin-1 has been proven effective in inhibiting tumors characterized by elevated p-MLKL levels, whereas a cytokine-rich environment results in a loss of viability. The absence of ATM increases radiosensitivity, suggesting a strategic combination with radiotherapy when the necroptotic pathway is activated (Liu et al., 2016[41]). In a related study, Cai et al. (2017[6]) found that TNF-alpha facilitates proliferation, colony formation, xenograft growth, and microvascular development via NF-kB. These effects can be mitigated through TNF/TNF receptor (TNFR) antagonism, indicating that survival mechanisms may be neutralized prior to the activation of pro-death pathways (Cai et al., 2017[6]). Additionally, He et al. (2021[24]) identified distinct roles for TNFR1 and TNFR2, demonstrating that the inhibition of TNFR2 alone can impede tumor growth and metastasis. This finding paves the way for future immunotherapy combinations that leverage rather than oppose receptor interactions (He et al., 2021[24]).

Fu et al. (2021[19]) implemented this concept in practice and discovered that the combination of anti-TNFR2 and anti-PD-L1 resulted in significant tumor efficacy, enhanced intratumor CD8+ T cells, reduced Tregs, and increased IFN-gamma levels, indicating that receptor-proximal rewiring can unlock checkpoint efficacy. Through a pro-apoptotic pharmacological approach, Yu et al. (2022[76]) demonstrated that a Smac mimetic combined with TRAIL significantly increased apoptosis and reduced xenograft burden compared to TRAIL alone, aligning with the early Chinnaiyan model and offering a feasible template in the context of a neutralized survival pathway (Fu et al., 2021[19], Yu et al., 2022[76]). The vascular invasion axis completes the cycle in triple-negative breast cancer. Li et al. (2023[38]) found that RIPK1 activation promotes vasculogenic mimicry, whereas RIPK1 inhibition eliminates it and is associated with denser but less favorable vascular remodeling and decreased survival, demonstrating that any cytotoxic or immune partner in the presence of vascular plasticity must involve RIPK1 regulation (Li et al., 2023[38]). Furthermore, Liu et al. (2023[42]) showed that Mlkl deletion prevents pulmonary dissemination and reduces soluble adhesion ligands by blocking ADAM10/17, with the antimetastatic effect relying on CD8+ T-cell activity; thus, the ability to assess immune responses to a necroptosis-based strategy is crucial (Liu et al., 2023[42]). Collectively, these findings support biomarker-guided pairing of TRAIL/Smac mimetics, RIPK1/MLKL inhibitors, and TNFR2 or PD-L1 blockade with cytotoxic agents and radiotherapy. Current priorities include optimizing sequencing to avoid cytokine rebound, integrating p-MLKL/TNFR bias as stratifiers, and conducting trials powered by immune and vascular pharmacodynamics alongside survival endpoints (Figure 6(Fig. 6)).

The authors declare no conflicts of interest. The authors have no financial relationships with the organization that sponsored the research.

Misbahuddin Rafeeq, Muhammad Afzal: Investigation, Writing-original draft & formal analysis; Muhammad Shahid Nadeem: Visualization; Alaa Hamed Habib: Formal analysis; Hadeel A Alsufyani: Formal analysis & data curation; Sami I. Alzarea: Resources, investigation & conceptualization; Omar Awad Alsaidan: Resources, investigation & conceptualization; Imran Kazmi: Supervision, investigation & conceptualization.

We declare that AI was not used for the preparation of this manuscript

This project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia under grant no. DRP-1-130-2025. The authors, therefore, acknowledge with thanks DSR for technical and financial support.