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Navigating resistance to immunotherapy in head-and-neck cancers: Mechanism and novel approaches
*Corresponding author: Abinash Patnaik, Department of Medical Oncology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India. abpatnaik2008@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Patnaik A, Sunny G, Yadav R. Navigating resistance to immunotherapy in head-and-neck cancers: Mechanism and novel approaches. Int J Mol Immuno Oncol. 2025;10:117-23. doi: 10.25259/IJMIO_25_2025
Abstract
Despite the transformative role of immune checkpoint inhibitors (ICIs) in the treatment of head-and-neck squamous cell carcinoma (HNSCC), the majority of patients either fail to respond or eventually relapse due to complex mechanisms of resistance. The inherent and extrinsic factors influencing ICI resistance in HNSCC are examined in this thorough review. Activation of oncogenic pathways, including PI3K and WNT/β-catenin, a high tumor mutational burden with loss of neoantigen expression, and poor antigen presentation are examples of intrinsic processes. Extrinsic processes include the immunosuppressive tumor microenvironment (TME), which is comprised of tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T-cells (T-regs), and the overexpression of other immune checkpoints such as TIM-3, TIGIT, and LAG-3. The review also discusses emerging strategies to overcome resistance, including the combination of ICIs with radiotherapy, targeted therapies, oncolytic viruses, cancer vaccines, toll-like receptor agonists, and nanotechnology-based delivery systems. In addition, precision medicine approaches – leveraging multi-omic profiling and patient-derived organoid models – offer promise for individualized immunotherapy. Novel cellular therapies, such as chimeric antigen receptor-T cells engineered to resist the immunosuppressive TME, are under investigation. Together, these advancements aim to reinvigorate antitumor immunity and expand the clinical benefit of immunotherapy in HNSCC.
Keywords
Head-and-neck squamous cell carcinoma
Immune checkpoint inhibitors
Immunotherapy
Resistance
INTRODUCTION
Head-and-neck squamous cell carcinoma (HNSCC) is a major global health concern, with more than 1.1 million new patients and 500,000 deaths annually, as per GLOBOCAN 2022. India carries a significant burden, especially in oral and oropharyngeal cancers, reporting over 200,000 new cases and 120,000 deaths each year, largely due to late diagnosis and limited treatment access. Tobacco, alcohol, and areca nut use are key risk factors, especially among men.[1] Immunotherapy, particularly PD-1 inhibitors such as pembrolizumab and nivolumab, has emerged as a valuable treatment option. While pembrolizumab improves outcomes in PD-L1–positive patients, overall response rates remain modest at around 20%.[2]
In this review, we give an update on the state of immunotherapy for patients with HNSCC, examine possible mechanisms causing resistance to immunotherapy, and explore the potential for the development of innovative strategies for overcoming resistance and improving outcomes.
TUMOR MICROENVIRONMENT (TME) AND IMMUNE ESCAPE MECHANISMS IN HNSCC
In HNSCC, the TME is crucial for immune evasion, treatment resistance, and cancer development. Myeloid-derived suppressor cells (MDSCs) are key immunosuppressive cells that hinder both innate and adaptive immunity by suppressing cytotoxic T lymphocytes (CTLs), impairing antigen presentation, promoting neovascularization, and influencing tumor-associated macrophage (TAM) differentiation. Driven by cytokines such as VEGF and IL-6, MDSCs also facilitate regulatory T cell (Treg) proliferation throuh IL-10, IFN-γ, and TGF-β, all contributing to poor prognosis and reduced response to immunotherapy.
TAMs, particularly the M2 phenotype, further suppress immune responses by expressing PD-L1 and secreting IL-10 and TGF-β. Their recruitment is supported by MDSCs through CSF-1 and MCP-1, especially under hypoxic conditions. Cancer-associated fibroblasts, activated by TGF-β and IL-1β, promote tumor growth and immune evasion by inhibiting T cells and attracting MDSCs and M2 macrophages.[3,4]
Immune checkpoints, particularly PD-1/PD-L1, are central to immune escape. Their inhibition restores CD8+ T cell activity, making them vital therapeutic targets. Other checkpoint molecules such as CTLA-4, TIM-3, LAG-3, indoleamine 2,3-dioxygenase 1 (IDO-1), GITR, VISTA, and NKG2A also contribute to immunosuppression. While pathways like STING offer promising activation of innate immunity, effective biomarker identification remains crucial for optimizing personalized immunotherapy in HNSCC.[2]
IMMUNOTHERAPY IN HNSCCS: HOW FAR HAVE WE REACHED?
Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1, has significantly advanced treatment in HNSCC. Agents such as pembrolizumab and nivolumab are being studied across treatment settings, from neoadjuvant to recurrent/metastatic disease, to improve survival and reduce toxicity. In resectable and locally advanced HNSCC, perioperative ICIs have shown promise. The KEYNOTE-689 trial demonstrated improved 3-year event-free survival in PD-L1-positive tumors with pembrolizumab, while other trials such as NCT02841748 and KEYNOTE-412 continue to explore its use.[2,5,6]
Nivolumab has shown modest to significant pathologic responses in neoadjuvant trials (e.g., CheckMate 358), and is being tested in combinations with chemoradiotherapy (CRT) or radiotherapy (RT), even in cisplatin-ineligible patients. Combination therapies involving dual ICIs (e.g., durvalumab + tremelimumab) show encouraging safety but uncertain T-cell infiltration benefits.[2,5,7]
In locally advanced disease, adding ICIs to RT or CRT has yielded mixed results. Trials such as KEYNOTE-412 showed good safety but no significant progression-free or overall survival benefits. Similarly, other agents such as avelumab and durvalumab, have yet to meet primary endpoints.[8]
In recurrent/metastatic settings, nivolumab and pembrolizumab have demonstrated clear survival advantages, particularly in platinum-refractory disease, with better toxicity profiles. First-line pembrolizumab, alone or with chemotherapy (KEYNOTE-048), is now standard in PD-L1 CPS ≥1 patients. However, other combination trials (e.g., CheckMate 651 and KESTREL) failed to meet survival endpoints, underscoring the need for refined biomarker-driven patient selection.[9-11]
MECHANISM OF RESISTANCE TO IMMUNOTHERAPY IN HNSCCS
ICIs have become a potent treatment option for HNSCC and other cancers. By targeting negative regulators of T-cell activation, particularly the PD-1/PD-L1 and CTLA-4 pathways, ICIs restore antitumor immune activity in a subset of patients. However, despite promising results, many patients with HNSCC do not benefit from ICIs, either failing to respond from the outset (primary resistance) or developing resistance after an initial response (secondary or acquired resistance). Resistance to ICIs can also be classified as intrinsic, due to tumor cell-autonomous mechanisms, or extrinsic, involving elements of the TME. Understanding the complex biology behind these resistance patterns is essential to improving outcomes and guiding future therapeutic strategies.[12,13]
Intrinsic Resistance Mechanisms in HNSCC
Impaired tumor immunogenicity and defective antigen presentation
HNSCC typically exhibits a high tumor mutational burden (TMB), which should theoretically enhance the generation of tumor-specific neoantigens and promote immune recognition. Higher TMB has been associated with better responses to ICIs in various cancers. However, many HNSCC tumors with high TMB do not respond to ICIs. A key reason is immune-driven tumor evolution, where subclonal populations lose expression of immunogenic neoantigens, enabling them to escape immune surveillance and rendering ICIs ineffective.[12,13]
Another critical resistance mechanism involves disruptions in the antigen presentation machinery. In HNSCC, downregulation of major histocompatibility complex class I (MHC-I) molecules and mutations in β2-microglobulin hinder antigen presentation to cytotoxic T cells. These impairments prevent effective recognition and killing of tumor cells. In addition, defects in signaling pathways essential for antigen processing, such as STAT1, further reduce tumor immunogenicity. These combined deficiencies not only impair T-cell priming and infiltration but also create an immunologically “cold” tumor environment resistant to immunotherapy. Thus, despite high TMB, the loss of neoantigen expression and dysfunctional antigen presentation are major obstacles that limit the effectiveness of ICIs in many HNSCC patients.[12,13]
Oncogenic pathways and immune modulation
Activation of specific oncogenic signaling pathways within HNSCC tumor cells also contributes to immune resistance by shaping the immunosuppressive TME. Aberrations in the MAPK, WNT/β-catenin, and PI3K pathways have been implicated in altering cytokine expression, immune cell recruitment, and immune evasion. Among these, the PI3K pathway has been shown to drive immune suppression by inhibiting effector T-cell responses and promoting regulatory mechanisms. Preclinical models demonstrate that combined blockade of PD-1 and PI3K leads to enhanced antitumor responses, increased survival, and a more immunostimulatory gene expression profile.[12,13]
Immunosuppressive soluble factors
Beyond intrinsic cellular mechanisms, HNSCC tumors secrete a variety of immunosuppressive molecules that inhibit effector immune responses. Tumor-derived exosomes containing molecules such as PD-1, CTLA-4, and TGF-β impair T and natural killer (NK) cell function, while promoting regulatory T cell (Treg) expansion. Cytokines such as IL-6 and IL-10 further suppress antigen presentation and T-cell activation. Another notable molecule is IDO1, which catalyzes tryptophan degradation into kynurenine, leading to T-cell energy and apoptosis. Although IDO1 inhibition appeared promising in preclinical models and early trials, the phase III trial of epacadostat plus pembrolizumab in melanoma failed to show added clinical benefit, leading to questions about its efficacy in HNSCC.[12-14]
Extrinsic resistance mechanisms and the TME
Immune checkpoint redundancy and alternative inhibitory molecules
A key extrinsic mechanism of resistance to immunotherapy in HNSCC involves the upregulation of alternative immune checkpoints beyond the well-known PD-1/PD-L1 and CTLA-4 pathways. These additional inhibitory receptors – including LAG-3, TIM-3, TIGIT, VISTA, and BTLA – are expressed on T cells, NK cells, and antigen-presenting cells, contributing to T cell exhaustion and resistance to ICIs. LAG-3, found on activated T cells and Tregs, binds MHC class II molecules and suppresses T-cell proliferation. TIM-3, often co-expressed with PD-1, is a marker of deeply exhausted T cells. In preclinical HNSCC models, blocking these alternative checkpoints has restored T-cell function and led to tumor regression, prompting clinical trials exploring dual or multi-checkpoint blockade strategies.[12,13]
However, clinical outcomes in HNSCC have been limited so far. Notably, the CONDOR and EAGLE trials tested durvalumab (anti-PD-L1) with tremelimumab (antiCTLA-4) but failed to show significant benefits over PDL1 blockade alone in terms of response rates or survival outcomes. One explanation for the underwhelming efficacy is that tremelimumab, an IgG2 antibody, lacks the antibody-dependent cellular cytotoxicity activity required to deplete Tregs, unlike ipilimumab, an IgG1 antibody with such capabilities.[12,13,15,16]
Innate immune checkpoints and NK cell modulation
In addition to their expression on adaptive immune cells, checkpoint molecules are also found on innate immune cells such as NK cells. The inhibitory killer immunoglobulin-like receptors (KIRs) regulate NK cell activity by interacting with HLA-C molecules on target cells. Lirilumab, a monoclonal antibody against KIRs, is being investigated as a means to enhance NK cell-mediated cytotoxicity. Interestingly, PD-1 blockade in T cells leads to increased IL-2 production, which in turn activates NK cells. A strong foundation for combination tactics that concurrently target both arms of the immune system is provided by the reciprocal interplay between NK and T cells.[12,13]
Costimulatory pathways
In addition to overcoming inhibitory signals, successful antitumor immunity also depends on the presence of costimulatory signals. Molecules such as OX40, 4-1BB (CD137), ICOS, and CD40 provide critical secondary signals that promote T-cell proliferation, cytokine production, and survival. In HNSCC, expression of these molecules or their ligands is often dysregulated. For example, while OX40 is expressed on T cells, its ligand OX40L is frequently underexpressed in tumors, diminishing the efficacy of the pathway.[12,13]
Several clinical trials are now testing costimulatory agonists, alone or in combination with ICIs, chemotherapy, or targeted therapies. ICOS agonists are being evaluated in combination with anti-PD-1 and anti-CTLA-4 antibodies in ongoing trials. Likewise, urelumab, a 4-1BB agonist, is being evaluated with cetuximab in recurrent/metastatic HNSCC. These approaches seek to restore the balance of inhibitory and stimulatory signals in the TME.[12,13,17]
Immunosuppressive cellular constituents of the TME
The TME in HNSCC contains multiple immunosuppressive cell types that facilitate immune evasion and resistance to immunotherapy. MDSCs are prominent in the TME, where they inhibit T-cell activation by producing enzymes such as arginase-1 and inducible nitric oxide synthase, which deplete nutrients critical for T-cell function. MDSCs also release reactive nitrogen species that disrupt T-cell receptor signaling and promote tumor angiogenesis, invasion, and metastasis. Their accumulation is linked to poor responses to ICIs. Therapies targeting MDSCs aim to block their function or recruitment using monoclonal antibodies and small molecules.
Regulatory T cells (Tregs), typically responsible for immune tolerance, are exploited by tumors to suppress antitumor immunity in HNSCC. These cells secrete immunosuppressive cytokines such as IL-10 and TGF-β and inhibit effector T-cell activity. Tregs express CCR4, aiding their migration into tumors. Anti-CCR4 agents, such as mogamulizumab, are under investigation to counteract their effects.
TAMs, especially the M2 subtype, promote immune suppression and tumor growth by releasing anti-inflammatory cytokines and supporting angiogenesis. Targeting TAMs through colony-stimulating factor 1 receptor (CSF1R) inhibitors is an emerging strategy being tested in clinical trials for advanced HNSCC.[12,13]
TACKLING RESISTANCE: FUTURE DIRECTIONS
Radiation therapy as an immune modulator
Radiation therapy, traditionally used to control tumors locally in HNSCC, also significantly influences the immune system. It induces immunogenic cell death, releasing tumor-associated antigens (TAA), danger signals, and pro-inflammatory cytokines that stimulate dendritic cell (DC) maturation and prime naïve T cells. This process can turn irradiated tumors into in situ vaccines, promoting systemic immune responses.
Radiation increases tumor cell expression of MHC-I and costimulatory molecules, enhancing recognition by cytotoxic T lymphocytes (CTLs). It also upregulates death receptors such as Fas and TNF-related apoptosis-inducing ligand receptor (TRAIL-R), aiding CTL and NK cell-mediated tumor destruction. The “abscopal effect,” where localized radiation leads to regression of distant tumors, highlights radiation’s systemic immune potential, especially when combined with ICIs such as anti-PD-1 or anti-CTLA-4.
Modern radiation techniques such as stereotactic body radiation therapy and hypofractionated regimens, deliver higher doses in fewer sessions, boosting immunogenicity and T-cell infiltration. However, radiation can also induce immunosuppressive effects, including increased PD-L1 expression and recruitment of T-regs and MDSCs, which may dampen immune responses. Therefore, it is crucial to optimize the timing and combination of radiation with ICIs. The objective of current clinical trials is to treat HNSCC by optimizing therapeutic synergy and reducing immune suppression.[18]
Targeting oncogenic pathways
The development and immunological resistance of HNSCC are mostly caused by dysregulated oncogenic signaling pathways. These pathways not only promote tumor growth and metastasis but also remodel the TME to evade immune detection. As a result, targeting these signaling networks has become a promising strategy to enhance immunotherapy effectiveness.
The PI3K/AKT/mTOR pathway is frequently hyperactivated in HNSCC due to mutations like phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) or phosphatase and tensin homolog (PTEN) loss. This activation fosters immunosuppression by producing inhibitory cytokines, reducing MHC-I expression, and recruiting regulatory T cells (Tregs) and MDSCs. Combining PI3K inhibitors with PD-1 blockade in preclinical models has shown synergistic effects, increasing T-cell infiltration and cytotoxicity while slowing tumor growth.
Epidermal growth factor receptor (EGFR) signaling, which is overexpressed in about 90% of HNSCC cases, is another key driver oncogene linked to poorer outcomes. Resistance to anti-EGFR therapies such as cetuximab involves mechanisms such as epithelial-mesenchymal transition and PD-L1 upregulation, which also promote immune evasion. Novel agents such as BCA101, which block both EGFR and TGF-β, aim to overcome these hurdles by restoring immune recognition and boosting checkpoint inhibitor responses.
Other pathways, including MAPK, Wnt/β-catenin, and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), contribute to immune escape by limiting DC recruitment and T-cell priming. Inhibiting β-catenin signaling, for example, can convert immune “cold” tumors into infiltrated ones, enhancing immunotherapy outcomes.
CDK4/6 inhibitors are emerging as dual-function agents that halt tumor cell proliferation and enhance antigen presentation while reducing Tregs. Their combination with ICIs has shown promising tumor control in early studies.
Finally, STAT3 promotes immunosuppressive factors and increases Tregs and MDSCs; it is frequently constitutively active in HNSCC. By focusing on STAT3, tumors can become more sensitive to immunotherapy by shifting the TME toward inflammation.
Overall, a potent strategy to undo tumor-induced immune suppression is to specifically target oncogenic pathways. Ongoing clinical trials combining these targeted agents with immunotherapies hold promise for more effective, personalized treatment strategies in HNSCC.[19]
Novel ICIs
While PD-1/PD-L1 and CTLA-4 blockade have achieved clinical success in HNSCC, many patients exhibit resistance or relapse, prompting investigation into alternative immune checkpoints involved in tumor immune evasion. Key emerging targets include LAG-3, TIM-3, TIGIT, VISTA, and BTLA, which contribute to T cell dysfunction and immune suppression within the TME.
LAG-3, expressed on activated T cells, Tregs, and NK cells, inhibits T-cell activation by binding MHC class II molecules and often co-expresses with PD-1 on exhausted T cells. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor effects, with clinical trials underway for resistant HNSCC. TIM-3, another exhaustion marker, interacts with ligands such as galectin-9, impairing T-cell function, and promoting apoptosis; TIM-3 inhibitors are in early trials, alone or combined with PD-1 blockade. TIGIT competes with activating receptors on T and NK cells, dampening immune responses; blocking TIGIT alongside PD-1 may restore effective immunity. VISTA, mainly on myeloid cells and Tregs, is upregulated after PD-1 therapy and contributes to resistance, making it a potential target for refractory patients. BTLA, binding herpesvirus entry mediator (HVEM), also suppresses T-cell activity, though its role in HNSCC is less studied.
Beyond T cells, innate immune checkpoints on NK cells, such as KIRs, regulate cytotoxicity. Antibodies such as lirilumab targeting KIRs aim to boost NK cell-mediated tumor killing. TIGIT inhibition may also enhance NK cell function.
Together, these novel checkpoints represent promising targets to overcome resistance by reinvigorating exhausted immune cells. Ongoing clinical trials and biomarker research will help personalize these next-generation immunotherapies for improved outcomes in HNSCC.[19]
Immunomodulatory combinations: Oncolytic viruses, vaccines, and TLR agonists
As monotherapies, ICIs often fail to elicit sufficient responses in many HNSCC patients because of the highly immunosuppressive TME. To address this limitation, researchers are increasingly evaluating immunomodulatory combinations that can reprogram the TME, enhance antigen presentation, and potentiate T cell-mediated immunity. Among the most optimistic strategies are oncolytic viruses, toll-like receptor (TLR) agonists, and cancer vaccines, each of which acts as an adjunct to ICIs by boosting the immune system’s ability for recognition and eradication of tumor cells.[19]
Oncolytic viruses
Genetically modified viruses, which selectively infect and destroy tumor cells while preserving healthy tissue, are used in oncolytic virus therapy. TAAs and danger-associated molecular patterns, which act as organic adjuvants that elicit both innate and adaptive immune responses, are released as a result of this lysis. In addition, these viruses can be engineered to express immune-stimulatory cytokines or checkpoint-inhibiting agents to amplify their immunogenicity.
The most extensively studied oncolytic virus is talimogene laherparepvec (TVEC), a modified herpes simplex virus type 1 that expresses granulocyte-macrophage colony-stimulating factor (GM-CSF) to promote DC recruitment and maturation. In HNSCC, TVEC has shown encouraging results when combined with pembrolizumab, especially in recurrent/metastatic (R/M) cases.[19]
Cancer vaccines
Cancer vaccines help to prime the immune system to recognize and eliminate tumor cells by introducing tumor-specific or associated antigens. These can be composed of peptides, whole proteins, nucleic acids (DNA/RNA), or even entire cells. The objective is to enhance antigen presentation and stimulate a robust cytotoxic T-cell response.
In HNSCC, vaccines targeting HPV-derived antigens such as E6 and E7 proteins have been explored, particularly in HPV-positive oropharyngeal cancers. These vaccines can be administered in conjunction with ICIs to improve response rates by increasing the pool of tumor-specific T cells available for activation. DC vaccines, in which autologous DCs are pulsed using tumor antigens ex vivo and reinfused into the patient, have shown potential in early-phase trials to overcome immune tolerance and resistance.[19]
TLR agonists
TLRs are innate immune receptors that detect pathogen-associated molecular patterns and initiate downstream immune activation. Agonists targeting TLR3, TLR7, TLR8, and TLR9 have been developed as immune adjuvants that can potentiate T cell priming and reverse immunosuppression within the TME.
TLR9 agonists, for example, stimulate plasmacytoid DCs to produce type I interferons, thereby enhancing antigen presentation and T-cell recruitment. In preclinical HNSCC models, TLR agonists have demonstrated the ability to upregulate MHC expression and pro-inflammatory cytokine release. Clinical trials, such as NCT02521870, are evaluating TLR agonists in combination with ICIs to determine their safety and synergistic efficacy.[19]
Synergistic potential
The rationale for combining these immunomodulatory strategies with ICIs is grounded in their complementary mechanisms of action. While ICIs lift the brakes on existing anti-tumor immune responses, oncolytic viruses, vaccines, and TLR agonists act to initiate or amplify these responses. Together, they can convert an immunologically “cold” tumor into a “hot” one, characterized by increased infiltration of activated effector T cells and enhanced sensitivity to checkpoint blockade. Optimizing the timing, dosing, and sequencing of these agents will be the key strategies to maximize their synergistic potential while minimizing toxicity. Advances in biomarker development and immune profiling will also enable better patient selection and monitoring of response. Ultimately, these combinatorial approaches represent a promising path forward in overcoming ICI resistance and improving durable outcomes in HNSCC.[19]
Advanced drug delivery and nanotechnology systems
Nanotechnology-based drug delivery systems are revolutionizing immunotherapy for HNSCC by improving the precision, efficacy, and safety of therapeutic agents. Conventional systemic delivery methods often lead to insufficient drug concentrations at the tumor site and cause systemic toxicity. To address this, researchers are developing various nanocarriers—such as lipid nanoparticles (LNPs), polymeric nanoparticles, exosomes, and stimuli-responsive particles—that enable controlled and targeted drug release within the TME. LNPs, initially popularized by RNA vaccines, are now used to deliver siRNA against PD-L1, enhancing tumor cell vulnerability to immune attack. Polymeric nanoparticles, crafted from materials like PLGA and PEG, allow customizable release profiles and targeted delivery to immune cells or tumors. These have been used effectively in combination therapies, such as co-delivering anti-PD-1 antibodies and STING agonists to convert “cold” tumors into immune-responsive “hot” tumors. Exosomes offer a natural and biocompatible platform for delivering complex biologics. Smart nanoparticles, responsive to tumor-specific cues like low pH or hypoxia, ensure site-specific activation. In addition, nanocarriers now enable delivery of mRNA and CRISPR/Cas9 for gene editing within tumors. Although challenges remain regarding scale-up, regulation, and distribution, nanotechnology holds strong potential to become a key component of future precision immunotherapy strategies in HNSCC.[13]
Chimeric antigen receptor (CAR)-T cell therapy and TME remodeling
Adoptive T-cell therapy, particularly CAR-T cells, has revolutionized hematologic cancers. However, translating this success to solid tumors like HNSCC is challenging due to antigen heterogeneity, dense stroma, and immunosuppressive milieu.
Recent approaches aim to engineer CAR-T cells to secrete IL-12, resist TGF-β signaling, or co-express checkpoint blockade molecules. In addition, bispecific CARs targeting both TAAs and immune suppressive checkpoints are under evaluation. Remodeling the TME with agents targeting Tregs, MDSCs, and TAMs also improves CAR-T efficacy.[20]
Precision medicine and organoid models
Precision medicine in HNSCC focuses on customizing treatment based on the unique molecular and immunologic features of each patient’s tumor. This personalized strategy is particularly relevant as immunotherapy, though promising, shows variable efficacy across patients. Two major innovations supporting this approach are multi-omic profiling and patient-derived organoid models. Multi-omic profiling integrates genomic and proteomic analyses to uncover mutations, gene expression changes, and immune signatures that influence responses to ICIs. For example, mutations in PIK3CA or antigen presentation defects can predict resistance to ICIs. Tools like the PaSSS algorithm help design targeted drug combinations based on each tumor’s molecular profile. Patient-derived organoids – 3D cultures that retain the original tumor’s complexity – enable testing of immunotherapies, including ICIs, vaccines, and oncolytic viruses. Advanced organoid models that include immune and stromal cells better replicate the TME and are increasingly used in adaptive clinical trials. Future advancements involve integrating real-time monitoring (e.g., circulating tumor DNA, immune profiling) and leveraging artificial intelligence to refine therapy selection. Expansion of organoid biobanks, increased access to multi-omic data, and cross-disciplinary collaboration will be crucial to completely realize the potential of precision oncology in improving survival and outcomes in HNSCC patients.[13]
CONCLUSION
Despite the success of ICIs in treating HNSCC, their effectiveness is often limited by intrinsic and extrinsic resistance mechanisms. Factors such as immune evasion, antigen presentation defects, and redundant checkpoint signaling contribute to therapeutic failure. To overcome resistance, novel strategies are being explored, including combining ICIs with RT, targeting oncogenic pathways, and utilizing agents such as oncolytic viruses, vaccines, and smart nanocarriers. Precision oncology tools such as multi-omic profiling and organoid models help identify predictive biomarkers for personalized therapy. Advances in CAR-T cells and TME remodeling further enhance immunotherapy potential in HNSCC.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent not required as there are no patients in this study.
Conflict of interest:
Rajan Yadav is on the Editorial Board of the Journal.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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