Changing the immune response to cancer using new combination treatments

Preventive vaccines are designed to reduce the risk of cancer by targeting oncogenic viral infections (Bautista and Lopez-Cortes, 2025). Currently, two vaccines are approved for cancer prevention: the human papillomavirus (HPV) vaccine and the hepatitis B virus (HBV) vaccine. Prophylactic HPV vaccines, available in bivalent and quadrivalent formulations, have demonstrated over 90% efficacy in preventing cervical cancer and other HPV-related malignancies (Brisson et al., 2020). These vaccines also confer indirect protection to men through herd immunity (Drolet et al., 2019). Similarly, HBV vaccination is a cornerstone of public health strategies to prevent HBV-induced HCC. Integration into national immunization programs has significantly decreased HBV incidence and reduced acute infections, particularly among children and adolescents (Chae and Tak, 2023). Vaccination at birth prevents chronic HBV infection in over 90% of cases. However, challenges persist in preventing vertical transmission, especially from hepatitis B e-antigen (HBeAg)-positive mothers (Chen et al., 2017). Advances such as Heplisav-B offer improved immunogenicity and safety over older vaccines like Engerix-B, providing enhanced protection for non-responders (Splawn et al., 2018). In addition, efforts are underway to develop therapeutic vaccines targeting chronic HBV by enhancing immune clearance where prophylactic vaccination is insufficient (Hudu et al., 2024).

Therapeutic vaccines are designed to induce an immune response against established tumors. These vaccines deliver tumor-specific or tumor-associated antigens (TAAs), to APCs, particularly DCs, which in turn activate CTLs to recognize and kill cancer cells (Saxena et al., 2021). The goals of therapeutic vaccines include halting tumor progression, eradicating residual disease, and preventing relapse. Technological advancements in whole-exome/genome sequencing and bioinformatics have enabled the identification of neoantigens—tumor-specific mutated proteins with high immunogenicity and low tolerance, enabling personalized vaccine design (Brandenburg et al., 2024). In addition to neoantigens, shared TAAs expressed across multiple tumor types are commonly targeted (Saxena et al., 2021). Therapeutic vaccines function by enhancing antigen presentation, stimulating DC maturation, and promoting durable T cell–mediated immune responses within the TME, where both innate (natural killer (NK) cells, macrophages, neutrophils) and adaptive (T and B cells) immune cells coordinate antitumor immunity (Fan et al., 2023).

To achieve these goals, various vaccine platforms have been developed. DNA, RNA, and peptide-based vaccines deliver tumor antigens in forms that are processed and presented by APCs, inducing CTL responses (Kyriakidis et al., 2021). Nanoparticle-based systems further enhance vaccine efficacy by stabilizing antigens, improving cellular uptake, and directing delivery to specific immune cell subsets (Brandenburg et al., 2024). Ex vivo–loaded DC vaccines involve isolating DCs from the patient, pulsing them with tumor antigens in vitro, and reinfusing them to generate a robust and targeted immune response (Chiang et al., 2013). Irradiated tumor cell vaccines use tumor cells that have been rendered non-replicative yet maintain antigenicity, often engineered to secrete immune-activating factors that boost T cell priming (Curry et al., 2016). A notable example is Sipuleucel-T, approved in 2010 for metastatic castration-resistant prostate cancer. This autologous DC-based vaccine loads patient-derived DCs with a prostate antigen (PAP-GM-CSF fusion protein) and reinfuses them to stimulate a targeted immune response (Kantoff et al., 2010) (Figure 1A).

Beyond conventional vaccines, innovative immunotherapeutic strategies continue to emerge. One of the most established is intravesical Bacillus Calmette–Guérin (BCG) therapy for early-stage non-muscle invasive bladder cancer (NMIBC). BCG elicits a strong, localized immune response that helps prevent tumor recurrence. For patients who fail BCG therapy, the FDA-approved gene therapy nadofaragene firadenovec (Adstiladrin) provides a new option. This therapy uses a replication-deficient adenoviral vector to deliver human interferon alfa-2b cDNA directly to the bladder, showing high complete response rates in Phase III trials (Konety et al., 2024; Narayan et al., 2024).

Ongoing clinical trials continue to expand the therapeutic landscape. At Memorial Sloan Kettering Cancer Center, an mRNA-based vaccine targeting pancreatic cancer has shown promise in Phase I trials. This personalized vaccine induced robust CD8⁺ T cell responses that persisted for up to 4 years and correlated with reduced relapse at a 3-year follow-up (Sethna et al., 2025). Overall, vaccine development for cancer treatment is one of the most developing fields currently. Future investigations and ongoing clinical trials will further delineate the optimal targets of the immune response, dosage and vaccine platforms, including their integration into combination therapies aimed at maximizing patient outcomes in the face of a heterogeneous disease landscape.

ACTs represent a transformative modality in cancer immunotherapy, involving the isolation, expansion, and reinfusion of autologous or allogeneic immune cells to enhance tumor eradication. Among ACT approaches, TILs and genetically engineered T cells are widely employed. The latter includes T cells modified to express transgenic TCRs or CARs. Unlike TILs and TCR-modified T cells, CAR T cells operate independently of MHC-mediated antigen presentation, enabling broader and more versatile targeting of TAAs, a property that has made them a cornerstone in adoptive immunotherapy strategies (Finck et al., 2022) (Figure 1C). CAR T cells have demonstrated remarkable clinical success in hematologic malignancies. To date, six CAR T therapies have received FDA approval: four targeting CD19 (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel) and two targeting BCMA (idecabtagene vicleucel and ciltacabtagene autoleucel) for multiple myeloma (Mitra et al., 2023). These therapies show high response rates in B-cell precursor ALL, large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), and relapsed/refractory multiple myeloma (RMM) (Zugasti et al., 2025; Goyco Vera et al., 2024). Clinical trials have also expanded to target CD22, showing promise in ALL, and further preclinical efforts include dual-targeting strategies to mitigate antigen loss and tumor escape (Abbasi et al., 2023; June et al., 2018).

Structurally, CARs comprise an scFv domain for antigen recognition, a hinge region, a transmembrane domain, and intracellular signaling domains such as CD3ζ and co-stimulatory elements (e.g., CD28 or 4-1BB), which define their generation and impact persistence and function (Safarzadeh Kozani et al., 2022). Second-generation CARs have become the clinical standard, offering enhanced cytotoxicity and memory formation (Hong et al., 2020). New designs now incorporate logic gating, cytokine expression, and safety switches to enhance control and efficacy. Despite success in blood cancers, CAR T cell efficacy in solid tumors remains limited due to several challenges: scarcity of tumor-specific antigens, risk of on-target off-tumor toxicity, antigen heterogeneity, and an immunosuppressive TME that impairs T cell trafficking and function. To overcome these barriers, innovative in vivo engineering strategies have emerged, aiming to simplify manufacturing and broaden applicability. One major innovation is in vivo CAR T cell generation, which bypasses ex vivo cell manipulation and instead employs targeted delivery systems, such as lipid nanoparticles (LNPs), polymeric nanoparticles, viral vectors (e.g., lentivirus, AAV), and bioinstructive scaffolds, to directly engineer immune cells within the body (Li et al., 2025; Hunter et al., 2025). Among these, LNP–mRNA systems have shown particular promise due to their transient expression profiles, lower immunogenicity, and scalable manufacturing, benefiting from platforms used in mRNA vaccines (Kim et al., 2024; Kyriakidis et al., 2021). For instance, maleimide-functionalized LNPs conjugated to CD3-targeting antibodies have successfully delivered CD19 CAR mRNA to splenic T cells in preclinical models, achieving effective B cell depletion with minimal liver toxicity. In addition, Cas9-packaging enveloped delivery vehicles (Cas9-EDVs) allow for simultaneous in vivo CAR insertion and gene editing (e.g., TRAC knockout), facilitating allogeneic cell generation while reducing graft-versus-host risks. Virus-mimetic fusogenic nanovesicles (FuNVs) present an alternative by directly inserting preformed CAR proteins into T cells, enabling transient functionality without gene integration (Li et al., 2025; Hunter et al., 2025).

However, the use of CAR T cells is not without risk. The two most significant adverse effects are CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) (Asghar et al., 2023). CRS results from excessive cytokine secretion following T cell activation, presenting with fever, hypotension, and potentially multiorgan dysfunction. ICANS often co-occurs with severe CRS and is characterized by neurologic symptoms such as confusion, seizures, and cerebral edema, likely due to cytokine-induced blood-brain barrier disruption (Santomasso et al., 2023).

As adoptive therapies expand, alternative effector cells like NK cells and macrophages are increasingly being explored for CAR engineering. These innate immune cells offer unique biological properties that may help overcome the limitations faced by CAR T cell therapies, particularly in solid tumors. A leading example of CAR NK development is FT596, the first-in-class, off-the-shelf, induced pluripotent stem-cell (iPSC)-derived CAR NK product. FT596 is genetically engineered to express a CD19-specific CAR, an IL-15 receptor fusion to enhance persistence, and a high-affinity CD16 Fc receptor to facilitate antibody-dependent cellular cytotoxicity (ADCC) (Lin et al., 2023; Bachanova et al., 2021; Rezvani, 2019). In a Phase I trial involving patients with relapsed or refractory B cell malignancies, FT596 demonstrated a favorable safety profile, including an absence of cytokine release syndrome (CRS), and encouraging antitumor activity, underscoring its potential as an allogeneic and low-toxicity platform (Ghobadi et al., 2025).

Parallel efforts have led to the development of CT-0508, a first-in-class autologous CAR macrophage therapy designed to target HER2-expressing solid tumors. This therapy not only mediates direct cytotoxicity through phagocytosis but also remodels the TME by enhancing antigen presentation and promoting T cell infiltration (Klichinsky et al., 2020; Morva et al., 2025). Early-phase clinical evaluation of CT-0508 has demonstrated feasibility, biological activity, and favorable tolerability in patients with advanced HER2-positive cancers (Reiss et al., 2022; Reiss et al., 2025). Complementing these clinical approaches, preclinical models of in vivo CAR macrophage engineering, using mannose-targeted LPNs or biodegradable polymeric carriers, have shown promising efficacy in difficult-to-treat tumors such as pancreatic and HCC (Dagher et al., 2023). These examples underscore the growing interest in using innate immune cells to overcome the limitations of CAR T therapy in solid tumors and expand the adoptive cell therapy toolkit.

Cytokines are small, soluble proteins that mediate cell-to-cell communication and regulate the activation, differentiation, and function of both innate and adaptive immune responses. These key regulators of immune responses have been explored as cancer therapeutics due to their ability to activate and expand immune effector cells (Berraondo et al., 2019). Interleukin-2 (IL-2) and interferon-alpha (IFN-α) were among the first cytokines used in oncology, showing clinical benefit in subsets of patients with metastatic melanoma and RCC by enhancing cytotoxic immune activity. However, their clinical use has been hindered by systemic toxicity, including vascular leak syndrome, neuropsychiatric effects, and multiorgan dysfunction, largely due to their pleiotropic nature (Saxton et al., 2023). To improve safety and efficacy, efforts have focused on engineering cytokines with extended half-lives (e.g., pegylation), tumor-targeted delivery systems, and combinations with other immunotherapies (Aung et al., 2023). Notably, combining cytokines with ICIs or mAbs is being investigated to boost antitumor immunity while minimizing adverse effects (Hansel et al., 2010). Advances in cytokine engineering and biomarker-driven approaches are expected to refine patient selection and therapeutic outcomes. To address the limitations of pleiotropy and systemic toxicity, cytokine mimetics have emerged as a promising strategy. Using computational design, de novo mimetics such as Neo-2/15, engineered by David Baker's lab, selectively engage IL-2 receptor βγ chains, avoiding CD25-mediated toxicities while enhancing effector T cell activity and antitumor efficacy (Silva et al., 2019). These mimetics offer improved pharmacokinetics, reduced off-target inflammation, and greater tumor selectivity. To enhance tumor targeting and minimize systemic exposure, a variety of delivery technologies are under development. Nanoparticle-based carriers, hydrogels, and immunocytokine conjugates offer controlled release, preferential tumor accumulation, and improved pharmacokinetics. For instance, LNP-encapsulated cytokine mRNAs (e.g., IL-7 + IL-21) delivered intratumorally induced strong CD8⁺ T cell responses and durable antitumor immunity in preclinical settings (Hamouda et al., 2024). Reviews highlight how nanocarriers enhance efficacy of cytokines via localized delivery while minimizing systemic toxicity (Wang et al., 2025).

OVs represent a novel class of cancer therapeutics capable of selectively infecting and lysing tumor cells while sparing normal tissues (Chen et al., 2023; Rivera-Orellana et al., 2025) (Figure 1D). Their antitumor activity is mediated through direct oncolysis and the induction of systemic immune responses (Ma et al., 2023). Upon infection, OVs induce cellular stress pathways and stimulate the release of type I interferons (IFNs), activating DCs, cytotoxic CD8⁺ T lymphocytes, and NK cells (Kaufman et al., 2015). Tumor lysis releases PAMPs and DAMPs, TAAs, and neoantigens, promoting both innate and adaptive immune activation (Sun et al., 2023). Among OVs, talimogene laherparepvec (T-VEC), a modified herpes simplex virus type 1 (HSV-1) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), is the most clinically advanced and FDA-approved for metastatic melanoma (Coffin, 2016). Clinical results from the OPTiM Phase III trial demonstrated improved overall and durable response rates compared to conventional therapies (Andtbacka et al., 2015). Other platforms under investigation include HSV-based vectors (e.g., HF10, HSV1716) (Reddy et al., 2024), adenoviruses (e.g., Oncorine, ONYX-015, CG0070) (Fukuhara et al., 2016; Geoerger et al., 2002), reovirus (e.g., Reolysin, targeting Ras-mutated tumors) (Norman and Lee, 2000), and vaccinia virus (e.g., JX-594, also expressing GM-CSF) (Cousin et al., 2022; Lee et al., 2023). These agents exploit tumor-specific vulnerabilities to enhance selectivity and immune engagement. OVs are increasingly evaluated in combination with ICIs, chemotherapy, and radiotherapy to amplify efficacy and overcome immune resistance. Ongoing developments focus on novel viral platforms, such as measles virus, Newcastle disease virus, and Zika virus, and biomarker-guided strategies to personalize therapy and expand clinical utility across diverse cancer types (Zhang and Rabkin, 2021).

Synthetic cationic helical polypeptides have emerged as a novel class of immunotherapeutic agents capable of inducing potent antitumor immune responses, particularly through the activation of APCs. These engineered polypeptides represent a promising strategy for the treatment of advanced and metastatic breast cancer by engaging critical innate immune pathways (Lee et al., 2024). Upon exposure, they activate key intracellular sensors including TLR9, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING) adaptor protein. This activation cascade leads to the production of IFNs, which in turn stimulate robust cytotoxic T cell responses directed against tumor cells (Vormehr et al., 2019). The therapeutic efficacy of these polypeptides is rooted in their precisely designed physicochemical properties—electrostatic charge, hydrophobicity, and helical secondary structure. These features enhance systemic activity, immunogenicity, and serum stability (Lee et al., 2024). Mechanistically, synthetic polypeptides induce endoplasmic reticulum (ER) stress in APCs, prompting the release of mitochondrial DNA (mtDNA) into the cytosol. This mtDNA acts as a danger signal that activates innate immune pathways, thereby augmenting inflammatory responses, enhancing antigen presentation, and promoting phagocytosis of tumor cells by APCs (Krysko et al., 2012). Among the different polypeptides investigated, protamine alpha (PTMA), P1, and PS exhibited distinct characteristics in terms of serum stability, hydrophilicity, and pro-inflammatory gene induction. The P1 polypeptide emerged as the most promising candidate due to its optimized helical conformation, achieved through the incorporation of ethylene glycol moieties. This structural refinement endowed P1 with superior serum stability, prolonged circulation time, and enhanced tumor accumulation (Lee et al., 2024). In preclinical models, P1 effectively suppressed tumor growth and promoted the infiltration of IFNγ-producing T cells into the TME. It also improved APC-mediated phagocytosis and supported memory T cell development, critical for achieving durable antitumor immunity. Combination therapy using P1 and anti-PD-1 checkpoint blockade further enhanced antitumor efficacy. This combinatorial approach synergistically activated both TLR9-MyD88 and c-GAS-STING pathways, leading to the phosphorylation and nuclear translocation of interferon regulatory factor 3 (p-IRF3), a central transcription factor for IFN production. In murine models of 4T1 breast cancer brain metastases, this strategy significantly reduced tumor burden and prolonged survival, with 25% of treated mice surviving up to 150 days without evidence of tumor recurrence (Lee et al., 2024). From a clinical perspective, synthetic cationic helical polypeptides offer multiple advantages, including synthetic tunability, selectivity for immune activation without inducing global inflammation, scalable production, and the potential for systemic administration with limited off-target effects (Zheng et al., 2025). However, some limitations remain, such as limited pharmacokinetic and toxicity data in humans, the need for improved tissue targeting in complex tumor environments, and uncertainty regarding long-term immune consequences of sustained innate activation (Svenson et al., 2022). Further optimization of their structure, formulation, and delivery platforms will be critical for successful translation into clinical practice (Weiss et al., 2022). The rational design of synthetic cationic helical polypeptides represents a transformative direction in cancer immunotherapy, particularly for solid tumors. P1's ability to trigger intracellular DNA sensors via ER stress-induced mtDNA release exemplifies its multifunctional immunostimulatory capacity. By integrating molecular engineering with immunologic insights, these polypeptides offer a versatile and effective platform for inducing systemic and durable antitumor responses.

The development of combination immunotherapy has become essential to overcoming the resistance mechanisms that limit the efficacy of ICIs as monotherapies. Dual checkpoint blockade, such as the combination of ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor), has demonstrated superior efficacy and received FDA approval for multiple cancers, including melanoma, NSCLC, RCC, HCC, and microsatellite instability-high (MSI-high) colorectal cancer (Livingstone et al., 2022; Olson et al., 2021; Wolchok et al., 2022; Butterfield and Najjar, 2024). The approval of nivolumab with the LAG-3 inhibitor relatlimab for advanced melanoma underscores the expanding therapeutic potential of targeting additional inhibitory receptors (Tawbi et al., 2022; Cillo et al., 2024). Combinations under clinical evaluation include PD-L1 inhibitors (atezolizumab and dostarlimab) with TIGIT (tiragolumab) or TIM-3 (cobolimab) antagonists, as well as bispecific antibodies (LY3415244) that engage multiple checkpoints (Cho et al., 2022; Rousseau et al., 2023; Hsu et al., 2024; Zhang et al., 2025; Acharya et al., 2020; Sauer et al., 2023; Hellmann et al., 2021). Beyond inhibitory checkpoints, costimulatory agents offer another promising avenue. These agents enhance T cell activation and effector function, especially when used alongside inhibitory ICIs. For instance, pembrolizumab (anti–PD-1) is being evaluated in combination with INBRX-106, an OX40 agonist, for advanced solid tumors (Postel-Vinay et al., 2023). Similarly, combinations of PD-1 inhibitors like pembrolizumab or spartalizumab with TRX518, a GITR agonist, are being tested in solid tumors and lymphomas (Geva et al., 2020). Cytokines are also being integrated into combination regimens to enhance immune activation. IL-12 and IFNs can promote a proinflammatory TME by enhancing DC activation and antigen presentation, while IL-2 supports T cell proliferation and survival. Ongoing studies are evaluating ICIs in combination with IL-12, IL-2, or IFNγ across indications such as melanoma, solid tumors, and lymphomas (Zibelman et al., 2023; Algazi et al., 2020).

ICIs are increasingly combined with conventional therapies to enhance immune priming and tumor clearance. Chemotherapy induces immunogenic cell death and facilitates antigen release, augmenting the effectiveness of checkpoint blockade. Clinical trials have evaluated combinations such as nivolumab with gemcitabine and cisplatin in esophageal squamous cell carcinoma, NSCLC, and advanced cervical cancer (Doki et al., 2022; Forde et al., 2022; van der Heijden et al., 2023), as well as atezolizumab with carboplatin and etoposide for SCLC (Horn et al., 2018; Galluzzi et al., 2020). Radiotherapy promotes a proinflammatory microenvironment and antigen exposure, with several trials exploring its synergy with ICIs in solid tumors. For instance, durvalumab (anti–PD-L1) and tremelimumab (anti–CTLA-4) have been tested in combination with hypofractionated radiotherapy for NSCLC (Chang et al., 2022; Schoenfeld et al., 2022; Galluzzi et al., 2023), while stereotactic radiotherapy combined with nivolumab and ipilimumab has shown efficacy in Merkel cell carcinoma (Kim et al., 2022). Neoadjuvant and adjuvant strategies that incorporate ICIs are being evaluated in early-stage clinical trials to improve long-term immune surveillance and prevent recurrence. Trials include neoadjuvant regimens such as dostarlimab for dMMR colorectal cancer, nivolumab plus ipilimumab for melanoma, atezolizumab for HER2-positive breast cancer, and pembrolizumab for early-stage NSCLC (Chalabi et al., 2024; Blank et al., 2024; Wakelee et al., 2023; Huober et al., 2022). Adjuvant applications of pembrolizumab and atezolizumab are being studied for NSCLC and RCC (Choueiri et al., 2021b; Felip et al., 2021). In parallel, ICIs are being integrated with targeted therapies, including tyrosine kinase inhibitors (TKIs) and anti-angiogenic agents, which normalize the tumor vasculature and enhance T cell infiltration. Pembrolizumab combined with lenvatinib or axitinib has shown success in RCC and endometrial carcinoma (Makker et al., 2022; Felip et al., 2021; Rini et al., 2019), while nivolumab with cabozantinib is approved for advanced RCC (Choueiri et al., 2021a). Additionally, anti-VEGF therapy combined with ICIs, such as atezolizumab plus bevacizumab, enhances T cell activation and is FDA-approved for HCC (Finn et al., 2020). Targeting oncogenic drivers in melanoma, the combination of atezolizumab with cobimetinib (anti-MEK) and vemurafenib (anti-BRAF) has been approved for BRAF-V600E-mutant melanoma (Ascierto et al., 2023).

Innovative approaches are rapidly expanding the therapeutic scope of immunotherapy. One major area of progress involves personalized neoantigen vaccines, which aim to elicit tumor-specific T cell responses. These vaccines are being evaluated in combination with ICIs, such as ipilimumab or nivolumab, in melanoma, NSCLC, urothelial carcinoma, and glioblastoma multiforme (Ott et al., 2017; Ott et al., 2020; Awad et al., 2022). Similarly, bispecific T cell engagers (e.g., blinatumomab and PSMA-targeting BiTEs) are designed to redirect T cells toward tumor cells and are under investigation in both solid and hematologic malignancies (Kamat et al., 2021; Deegen et al., 2021). Another promising avenue involves the integration of adoptive cell therapy with ICIs. CAR T cell therapies co-administered with PD-1 or PD-L1 inhibitors are being explored to overcome T cell exhaustion and the immunosuppressive TME (Zhao et al., 2015; Grosser et al., 2019). In parallel, IL-15 superagonists such as N-803 have shown the potential to enhance CAR T cell persistence and antitumor efficacy in both preclinical and early-phase clinical studies (Romee et al., 2018; Lui et al., 2023). Radiotherapy is also being combined with ICIs to potentiate immune responses by promoting antigen exposure and proinflammatory signaling. Hypofractionated and stereotactic radiotherapy regimens have been tested with durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor) in NSCLC (Pakkala et al., 2020; Twyman-Saint Victor et al., 2015; Zhang et al., 2022), and in combination with nivolumab and ipilimumab in Merkel cell carcinoma (Kim et al., 2022). These approaches aim to convert immunologically "cold" tumors into "hot" ones that are more susceptible to immune attack. OVs, such as T-VEC, have also demonstrated synergy with ICIs by inducing immunogenic cell death and amplifying systemic immune activation, particularly in melanoma (LaRocca and Warner, 2018; Dong et al., 2023). In parallel, metabolic modulators are being developed to counteract immunosuppressive metabolites like lactate within the tumor microenvironment, thereby restoring T cell function (Zheng et al., 2024). Another Frontier in combination immunotherapy involves modulation of the gut microbiota. Probiotics, prebiotics, and dietary interventions are being tested as adjuncts to ICIs to enhance systemic immune tone and therapeutic response (Lu et al., 2022). Finally, novel multi-checkpoint blockade strategies are emerging. A recent neoadjuvant regimen involving simultaneous inhibition of PD-1, CTLA-4, and LAG-3 demonstrated durable tumor control in glioblastoma, with no recurrence at 17 months. This promising result has prompted the launch of a dedicated clinical trial (GIANT, NCT06816927) to further investigate this triple-combination approach (Long et al., 2025). Together, these innovative combination strategies exemplify the future of precision immuno-oncology, offering the potential to overcome therapeutic resistance, enhance efficacy, and deliver durable benefit across a wide range of tumor types.