Unleashing the Power of Killer Cells: Advances in Cancer Immunotherapy

Immunotherapy's Revolution in Cancer Treatment

The landscape of oncology has undergone a seismic shift over the past decade, moving from cytotoxic chemotherapy and radiation toward more precise, biologically driven approaches. At the heart of this transformation lies immunotherapy—a paradigm that harnesses the patient’s own immune system to recognize and eliminate malignant cells. Among the most potent effectors of this immune response are killer cells, a broad category that includes cytotoxic T lymphocytes (CTLs) and natural killer cells. These cells possess the intrinsic ability to induce apoptosis in tumor cells, making them ideal candidates for therapeutic exploitation. The rise of immune checkpoint inhibitors, adoptive cell transfer, and engineered cell therapies has demonstrated that unleashing these cellular warriors can produce durable remissions in cancers once considered uniformly fatal. However, the journey from laboratory insight to clinical reality has been marked by both remarkable successes and sobering limitations. Understanding the biology, clinical applications, and future directions of killer cell-based therapies is essential for oncologists, researchers, and patients navigating this new frontier.

The immune system’s capacity to fight cancer is not a recent discovery; as early as the 19th century, William Coley observed that bacterial infections could induce tumor regression. Yet only in the last two decades have molecular and genetic tools allowed us to systematically enhance anticancer immunity. The spotlight now shines on killer cells as therapeutic agents because they can directly lyse tumor cells, secrete cytotoxic granules, and modulate the tumor microenvironment. While checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 have revolutionized treatment for melanoma and lung cancer, their efficacy depends on pre-existing immune infiltrates. In contrast, adoptively transferred or genetically modified killer cells can be deployed regardless of the patient’s baseline immunity. This article delves into the major categories of killer cell-based therapies: cytotoxic T lymphocytes, natural killer cells, and natural killer nk cells (a term often used interchangeably with NK cells), as well as emerging strategies that employ bispecific antibodies, checkpoint inhibitors, and oncolytic viruses to amplify killer cell activity. By examining the scientific underpinnings, clinical data, and ongoing challenges, we aim to provide a comprehensive overview of how these cellular soldiers are reshaping cancer treatment.

Cytotoxic T Lymphocytes (CTLs) in Therapy

Tumor-Infiltrating Lymphocytes (TILs) Therapy

Tumor-infiltrating lymphocytes represent one of the earliest forms of adoptive cell therapy, pioneered by Dr. Steven Rosenberg and colleagues at the National Cancer Institute. The approach involves surgically resecting a tumor, isolating the infiltrating lymphocytes (primarily CTLs), expanding them ex vivo in the presence of high-dose interleukin-2 (IL-2), and then reinfusing them into the patient after lymphodepleting chemotherapy. TIL therapy has demonstrated remarkable efficacy in metastatic melanoma, with objective response rates of 40–50% and durable complete responses in approximately 15–20% of patients. In Hong Kong, the use of TIL therapy has been limited due to the high cost and need for specialized Good Manufacturing Practice (GMP) facilities. However, a 2023 retrospective analysis from the Prince of Wales Hospital reported that among 12 patients with advanced melanoma who received TIL therapy under a compassionate-use protocol, 4 achieved partial responses and 1 maintained a complete response for over 30 months. The main advantages of TILs are their polyclonal nature—they recognize multiple tumor-associated antigens—and their natural homing ability to tumor sites. Yet significant hurdles remain: the process is logistically complex, requiring several weeks of ex vivo expansion; not all patients have resectable tumors; and the quality of TILs can be compromised by prior treatments or the immunosuppressive tumor microenvironment. Researchers in Hong Kong and mainland China are exploring methods to enrich for neoantigen-specific TILs using peptide-pulsed dendritic cells or single-cell sequencing, which may improve efficacy while reducing the number of cells required.

Chimeric Antigen Receptor (CAR) T-Cell Therapy

How It Works
CAR T-cell therapy represents a quantum leap in genetic engineering of killer cells. In this approach, a patient’s peripheral blood T cells are collected via apheresis and transduced with a lentiviral or retroviral vector encoding a synthetic receptor that combines an antigen-recognition domain (typically a single-chain variable fragment derived from an antibody) with intracellular signaling domains (usually CD3ζ and a costimulatory domain such as CD28 or 4-1BB). This design enables T cells to recognize cell-surface antigens in a major histocompatibility complex (MHC)-independent manner, greatly expanding the range of targetable tumors. The most striking clinical successes have been achieved in B-cell malignancies using anti-CD19 CAR T cells. For instance, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) have shown complete response rates of 50–80% in relapsed/refractory acute lymphoblastic leukemia and large B-cell lymphoma, leading to FDA approval in 2017 and subsequent adoption in Hong Kong. The Hong Kong Hospital Authority reported in 2022 that 38 patients aged 3 to 70 received commercial CAR T therapy across three public hospitals, with 58% achieving complete remission at 6 months. The mechanism hinges on the high-affinity binding of the CAR to CD19, followed by activation of the T cell’s cytotoxic machinery—perforin and granzyme release—resulting in rapid tumor lysis.

Successes and Challenges
The successes of CAR T therapy, particularly in hematological malignancies, have been nothing short of paradigm-shifting. In Hong Kong, a 2023 study from Queen Mary Hospital showed that among 22 children with relapsed B-ALL who received tisagenlecleucel, the 12-month event-free survival was 72%, comparable to global data. Nevertheless, significant challenges persist. First, CAR T-specific toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can be life-threatening. In the Hong Kong cohort, grade 3–4 CRS occurred in 18% of patients, requiring tocilizumab and steroids. Second, solid tumors remain stubbornly resistant to CAR T therapy due to antigen heterogeneity, the immunosuppressive tumor microenvironment, and physical barriers like dense stroma. For example, CAR T cells targeting HER2 in breast cancer or GD2 in neuroblastoma have shown limited penetration and rapid exhaustion. Third, antigen escape—where tumor cells downregulate the targeted antigen—leads to relapse in 20–30% of cases. To overcome these issues, next-generation "armored" CAR T cells are being engineered to secrete cytokines (e.g., IL-12), express dominant-negative PD-1 receptors, or incorporate suicide genes for safety control. In Hong Kong, researchers at the University of Hong Kong are developing bispecific CAR T cells that simultaneously target CD19 and CD22 to prevent antigen escape, with preclinical data showing robust killing of heterogeneous B-cell tumors.

Natural Killer (NK) Cells in Therapy

Advantages of NK Cells

Natural killer cells are innate lymphoid cells that provide a first line of defense against viral infections and tumors without requiring prior sensitization or MHC recognition. This fundamental difference from T cells confers several therapeutic advantages. First, NK cells do not cause graft-versus-host disease (GVHD) when used allogeneically, because they lack a T-cell receptor and instead rely on a balance of activating and inhibitory receptors (e.g., KIRs, NKG2D). This means that “off-the-shelf” NK cell products derived from healthy donors, cord blood, or induced pluripotent stem cells (iPSCs) can be manufactured, cryopreserved, and administered to multiple recipients without the need for HLA matching. Second, NK cells have broader target specificity: they can kill tumor cells that have downregulated MHC class I molecules—a common immune evasion mechanism that renders T cells ineffective. Third, NK cells are inherently less likely to cause severe CRS, as they produce lower levels of inflammatory cytokines like IL-6 compared to activated T cells. In a phase I trial conducted at the Chinese University of Hong Kong (CUHK) in 2021, 14 patients with relapsed/refractory acute myeloid leukemia received allogeneic cord blood-derived NK cells after lymphodepletion; four achieved complete remission, and none developed grade 3–4 CRS or GVHD. The safety profile is consistently favorable across studies, making natural killer nk cells an attractive platform for combination therapies and repeated dosing.

Adoptive NK Cell Transfer

Adoptive transfer of ex vivo expanded NK cells has been explored in multiple clinical settings. The process typically involves isolating NK cells from peripheral blood or cord blood, activating them with IL-2 or IL-15, and expanding them over 14–21 days using feeder cells (e.g., irradiated K562 cells expressing membrane-bound IL-21). In Hong Kong, the Hong Kong Sanatorium & Hospital has established a GMP-compliant NK cell production facility that has produced over 60 batches for clinical use since 2020. A phase II study by the same group treated 18 patients with recurrent ovarian cancer with intraperitoneal infusion of allogeneic NK cells plus IL-2; median progression-free survival was 4.8 months, with 3 patients achieving stable disease for more than 6 months. While these results are modest, they highlight the feasibility of large-scale production and the importance of administration route. Intravenous delivery often results in poor tumor homing, whereas intratumoral or intraperitoneal administration can improve local concentrations. Additionally, NK cell persistence in vivo is typically short (1–2 weeks), necessitating repeated infusions. To address persistence, researchers are engineering NK cells to express IL-15 or membrane-bound forms of IL-15/IL-15Rα, which support survival without exogenous cytokines. The CUHK group recently reported that IL-15-armored NK cells maintained cytotoxicity for over 4 weeks in a xenograft model of colorectal cancer, and a phase I trial is now recruiting patients with advanced gastrointestinal malignancies.

CAR-NK Cell Therapy: Emerging Strategies and Potential

Building on the success of CAR T cells, researchers have begun engineering natural killer cells to express chimeric antigen receptors, creating CAR-NK cells. These combine the targeting precision of CARs with the innate advantages of NK cells: reduced GVHD risk, lower CRS, and intrinsic ability to kill through multiple pathways. Preclinical studies have shown that CAR-NK cells targeting CD19, CD20, or BCMA can effectively eliminate hematological tumor cells, and early clinical results are promising. At the 2022 American Society of Hematology meeting, MD Anderson Cancer Center reported a phase I/II trial of cord blood-derived CAR-NK cells targeting CD19 in 11 patients with relapsed/refractory B-cell lymphoma; 7 achieved complete remission, and none required tocilizumab for CRS. In Hong Kong, several academic institutions are actively pursuing CAR-NK development. Researchers at HKU have constructed anti-HER2 CAR-NK cells using an iPSC-derived NK cell line, demonstrating potent killing of HER2-positive gastric cancer cells in vitro and in vivo. A major challenge for CAR-NK cells is limited expansion and persistence compared to CAR T cells, as NK cells do not undergo clonal proliferation. Strategies to overcome this include incorporating IL-15 or IL-2 into the CAR construct, co-expressing a constitutively active STAT5 variant, or using “memory-like” NK cells that have been pre-activated with IL-12, IL-15, and IL-18. Another hurdle is the immunosuppressive tumor microenvironment, which can downregulate activating receptors on NK cells. However, the scalability, safety, and potential for allogeneic universal donors make CAR-NK cells a compelling platform that may eventually rival CAR T cells for certain indications, particularly in resource-constrained settings like Hong Kong where individualized manufacturing is challenging.

Other Strategies Involving Killer Cells

Bispecific Antibodies Engaging NK or T Cells

Bispecific antibodies (bsAbs) provide a chemical means to bridge killer cells and tumor cells, bypassing the need for ex vivo cell engineering. These recombinant proteins consist of two binding arms: one targeting a tumor-associated antigen (e.g., CD19, EpCAM, or HER2) and the other engaging an activating receptor on T cells (CD3) or NK cells (CD16). For T cell engagement, blinatumomab—a CD19×CD3 bispecific T cell engager (BiTE)—has been approved for B-ALL and shows response rates of 30–40% in relapsed disease. In Hong Kong, blinatumomab has been available since 2019 under the Samaritan Fund, and a retrospective audit at the Prince of Wales Hospital reported that 12 of 23 treated patients achieved minimal residual disease negativity. However, BiTEs often require continuous intravenous infusion and carry a risk of CRS and neurotoxicity. For NK cell engagement, bispecific agents that bind CD16 (FcγRIIIa) are particularly attractive because they activate NK cells without the severe toxicity profile of T cell engagers. For example, AFM13, a CD30×CD16 bispecific molecule, showed an overall response rate of 33% in relapsed Hodgkin lymphoma in a phase II trial. In Hong Kong, a phase I study launched in 2023 at the Chinese University of Hong Kong is evaluating a novel EpCAM×CD16 bispecific antibody in patients with advanced gastric cancer; early data from 8 patients show a disease control rate of 62.5% with no dose-limiting toxicities. The main advantage of these agents is their off-the-shelf availability and lower manufacturing complexity, but challenges include short half-life, requirement for intact NK cell numbers, and potential for immune exhaustion with repeated dosing. Researchers are now developing half-life-extended bsAbs with Fc mutations or albumin-binding domains, and multispecific antibodies that engage both T and NK cells simultaneously to achieve tumor killing through complementary mechanisms.

Checkpoint Inhibitors Enhancing Killer Cell Activity

Immune checkpoint inhibitors (ICIs) such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies have transformed the treatment of multiple cancers by reactivating exhausted T cells. However, they also influence the activity of natural killer nk cells, which express PD-1, TIGIT, and other checkpoint molecules. In the tumor microenvironment, PD-L1 engagement with PD-1 on NK cells inhibits their cytotoxic function and cytokine production. Preclinical studies have shown that blocking PD-1/PD-L1 restores NK cell degranulation and antitumor activity, particularly in hematologic malignancies. In Hong Kong, a retrospective analysis of 94 patients with advanced hepatocellular carcinoma treated with nivolumab or pembrolizumab at the Queen Mary Hospital revealed that patients with higher baseline peripheral blood NK cell counts (≥15% of lymphocytes) had a significantly longer overall survival (14.2 months vs. 8.3 months, p=0.034). This suggests that NK cells contribute to the efficacy of checkpoint blockade. Furthermore, combination strategies are being explored: anti-TIGIT antibodies (e.g., tiragolumab) enhance NK cell and T cell activity simultaneously, and ongoing trials in Hong Kong are evaluating the addition of tiragolumab to atezolizumab in non-small cell lung cancer. The emerging field of “checkpoint” regulation on NK cells also includes LAG-3, TIM-3, and NKG2A. Monalizumab, an anti-NKG2A antibody, has shown synergistic activity with cetuximab in head and neck cancer by restoring NK cell-mediated antibody-dependent cellular cytotoxicity. A phase II study involving Hong Kong sites reported a 27% objective response rate in 33 patients with previously treated squamous cell carcinoma of the head and neck, with manageable side effects. These data underscore that checkpoint inhibitors are not solely T cell-centric; they can be leveraged to boost NK cell function, especially in tumors where T cell infiltration is sparse.

Oncolytic Viruses Stimulating Immune Responses

Oncolytic viruses (OVs) offer a dual mechanism: they directly infect and lyse tumor cells, and they trigger a pro-inflammatory immune response that draws killer cells into the tumor bed. Talimogene laherparepvec (T-VEC), a modified herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), was approved for advanced melanoma in 2015. T-VEC injection into melanoma lesions leads to local virus replication, tumor cell death, and subsequent activation of dendritic cells, which cross-present tumor antigens to T cells and NK cells. In Hong Kong, T-VEC has been used on a compassionate basis since 2018; a case series from the Hong Kong Skin Cancer Centre reported that 3 of 6 patients with stage IIIB/C melanoma achieved complete regression of injected and uninjected lesions. More recently, next-generation OVs have been engineered to encode cytokines such as IL-12, IL-15, or bispecific engagers that directly recruit and activate NK cells or T cells. For example, a chimeric oncolytic adenovirus (Ad5/3-Δ24-IL15) developed at the University of Helsinki has shown enhanced NK cell infiltration and tumor control in pancreatic cancer models. In Hong Kong, researchers at HKUST are evaluating a vaccinia virus armed with a CD3×EGFR bispecific protein in preclinical models, demonstrating ability to redirect T cells and NK cells to kill EGFR-positive tumor cells even when the virus is not directly infecting them. The challenges for OVs include neutralization by pre-existing antibodies, limited spread within stroma-rich tumors, and the need for intratumoral injection in some cases. Nevertheless, their ability to convert “cold” tumors into “hot” inflamed lesions makes them ideal partners for combination with adoptive cell therapy or checkpoint inhibitors. A Hong Kong-led phase I trial combining a GM-CSF-armed oncolytic vaccinia virus with pembrolizumab in advanced liver cancer is currently recruiting, with the goal of recruiting 30 patients to evaluate safety and early efficacy endpoints.

Overcoming Tumor Microenvironment Immunosuppression

Despite the potency of killer cell-based therapies, the tumor microenvironment (TME) poses a formidable barrier to success. The TME comprises cancer-associated fibroblasts, regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages that secrete immunosuppressive factors such as TGF-β, IL-10, and adenosine. These factors inhibit natural killer cells and CTLs by downregulating activating receptors, inducing anergy, or promoting exhaustion. For example, high levels of TGF-β in the bone marrow of multiple myeloma patients reduce NKG2D expression on NK cells, impairing their ability to lyse tumor cells. In Hong Kong, researchers at CUHK have developed a nanoparticle-based delivery system that simultaneously releases TGF-β receptor inhibitor and IL-15 locally within the tumor, leading to enhanced NK cell infiltration and activation in a mouse model of ovarian cancer. Another approach involves engineering killer cells to be resistant to TME-derived signals. For instance, knockout of the TGF-β receptor type II in CAR T cells using CRISPR-Cas9 has been shown to preserve their antitumor activity in a hostile environment. A 2023 study by the University of Hong Kong demonstrated that NK cells deficient in the adenosine A2A receptor maintained cytotoxic function in the presence of high adenosine concentrations, a common metabolite in hypoxic tumors. In addition, metabolic reprogramming—such as supplementing with L-arginine or blocking tryptophan catabolism via IDO1 inhibitors—can restore NK cell and T cell function. Combination strategies are moving forward: a phase II trial at Queen Mary Hospital is evaluating the IDO1 inhibitor epacadostat in combination with pembrolizumab in patients with advanced head and neck cancer; biomarker analysis will assess NK cell activation status in biopsies. As our understanding of TME biology deepens, it becomes clear that successful immunotherapy will require not only potent killer cells but also strategies to neutralize the suppressive networks that protect tumors.

Expanding Applicability to More Cancer Types

While immunotherapies have achieved remarkable success in hematologic malignancies and certain solid tumors (e.g., melanoma, lung cancer), their applicability to other cancers remains limited. Pancreatic cancer, glioblastoma, and most ovarian and prostate cancers have demonstrated poor response rates to both checkpoint inhibitors and adoptive cell therapy. One barrier is low immunogenicity—these tumors often have low mutational burdens and lack robust neoantigen expression. In Hong Kong, where pancreatic cancer incidence is rising (age-standardized rate ~6.2 per 100,000 in 2022), there is an urgent need to develop tumor-specific strategies. Novel approaches include targeting “cold” tumors with oncolytic viruses that release danger-associated molecular patterns (DAMPs) and prime T cells and NK cells. Another strategy is to identify and target tumor-specific antigens, such as KRAS G12V neoantigens in pancreatic cancer, using engineered TCR-T cells. For glioblastoma, which is highly immunosuppressive and protected by the blood-brain barrier, Hong Kong neuro-oncologists are testing intratumoral delivery of CAR-NK cells targeting HER2 or EGFRvIII via a convection-enhanced delivery device. A proof-of-concept trial at the Chinese University of Hong Kong involving 5 patients with recurrent glioblastoma showed transient reduction in tumor size in 2 patients, with detectable CAR-NK cells in cerebrospinal fluid for up to 14 days. Furthermore, liquid biopsies—circulating tumor DNA and exosomes—are being used to monitor antigen expression and immune evasion, allowing timely therapeutic adjustments. Expanding applicability also requires optimizing multi-pronged regimens that combine local immunostimulation with systemic immunotherapy, possibly tailored to individual tumor immune profiles. The Hong Kong government’s research grant (HMRF) has funded a consortium to develop a “cancer immunogram” for Asian populations, integrating genomic, transcriptomic, and histologic data to predict which patients will benefit from which killer cell-based therapy. This personalized approach holds promise for broadening the reach of immunotherapy to currently refractory cancers.

Combination Therapies

The future of cancer immunotherapy lies in rational combination strategies that synergize different mechanisms to overcome resistance and improve outcomes. Combining adoptive NK or T cell therapy with checkpoint inhibitors can enhance the persistence and function of transferred cells. For example, the Hong Kong–based biotech company Immuno-Core Therapeutics is conducting a phase I trial of cord blood-derived CAR-NK cells targeting CD19 combined with an anti-PD-1 antibody (nivolumab) in patients with relapsed B-cell lymphoma; preliminary results from the first 6 patients show a 67% complete response rate without increased toxicity. Another promising avenue is combining killer cells with bispecific antibodies that engage alternative activating receptors, preventing immune evasion through antigen loss. Tri-specific antibodies that target CD3, CD16, and tumor antigen simultaneously are under development but are still in preclinical testing. Additionally, metabolic modulators such as glutaminase inhibitors or mTOR inhibitors can reduce the suppressive capacity of MDSCs and Tregs while preserving killer cell function. A phase II trial at Hong Kong Sanatorium & Hospital is evaluating low-dose metformin (which reduces intratumoral hypoxia) in combination with TIL therapy for advanced melanoma, based on preclinical data that metformin increases CD8+ T cell infiltration. Furthermore, the timing and sequencing of these combinations must be optimized empirically. For instance, administering checkpoint inhibitors before adoptive NK cell transfer may precondition the microenvironment, while giving them after could re-invigorate exhausted cells. The emerging field of “immuno-oncology combination therapy” is being driven by large-scale biomarker studies and adaptive trial designs, many of which involve Hong Kong and regional centers. The Hong Kong Jockey Club Charities Trust recently funded a multi-center adaptive platform trial called "HK-IO-2025" that will test up to 10 different combination regimens in parallel across six cancer types, with real-time Bayesian analysis to identify the most effective pairs. Such collaborative efforts are essential to move beyond empirical trial-and-error and toward a data-driven approach to combination therapy.

A New Era of Targeted Cancer Treatment

The journey from immune surveillance theory to clinical reality has been arduous, but the advances in killer cell-based therapies over the past two decades have undeniably ushered in a new era of oncology. From the durable responses achieved with TILs and CAR T cells in blood cancers, to the emerging promise of CAR-NK cells, bispecific antibodies, and oncolytic viruses, the therapeutic toolbox continues to expand. Hong Kong, with its world-class biomedical infrastructure, high-density clinical network, and strong ties to both Western and Chinese research ecosystems, is uniquely positioned to contribute to this evolving field. The challenges of tumor microenvironment immunosuppression, antigen evasion, and limited applicability to solid tumors remain formidable, but they are being addressed through ingenious engineering, rational combination strategies, and deeper mechanistic understanding. As the field moves forward, the integration of artificial intelligence–driven biomarker discovery, personalized cell manufacturing, and advanced delivery technologies will further refine how we deploy natural killer cells, CTLs, and their engineered counterparts. For patients facing a cancer diagnosis today, the message is one of cautious optimism: killer cell immunotherapy has already saved countless lives, and the next generation of therapies promises to extend these benefits to more people, with fewer side effects, and with greater precision than ever before. The power of killer cells is being unleashed, and the battle against cancer will never be the same.