Is Trastuzumab Immunotherapy or Targeted Therapy?

Trastuzumab is both. It was developed and approved as a targeted therapy, and that label stuck in clinical oncology guidelines, but its mechanism of action involves a substantial immune component that qualifies it as immunotherapy too. The drug is a monoclonal antibody that latches onto a specific protein on cancer cells called HER2, blocking the growth signals that protein sends. At the same time, it recruits the patient’s own immune cells to attack those cancer cells. The classification debate is not just academic naming: which mechanism dominates in a given patient can influence how well the drug works and which combination treatments make sense.

What Trastuzumab Actually Does to Cancer Cells

HER2 is a receptor protein that sits on the surface of cells and, when activated, tells them to grow and divide. In healthy tissue that signaling is tightly controlled. But in roughly 15 to 30 percent of breast cancers and a similar fraction of gastric cancers, the gene coding for HER2 is amplified or the protein is overexpressed, flooding the cell surface with receptors that pair up and fire growth signals without the usual controls.¹ When HER2 is overexpressed, it can spontaneously form pairs with itself or with related receptors, triggering downstream pathways that drive tumor growth.²

Trastuzumab is a humanized monoclonal antibody engineered to bind tightly to the outer portion of the HER2 receptor. Once bound, it does several things on the “targeted therapy” side of the ledger. It physically blocks the receptor from pairing with partner receptors, which disrupts the signaling complexes that tell the cell to keep dividing.³ It also inhibits a process called ectodomain cleavage, where the outer part of HER2 gets snipped off, leaving behind a truncated fragment that is constitutively active and harder for therapies to reach.⁴ And it speeds up internalization and degradation of HER2 from the cell surface, reducing the number of receptors available to drive growth.⁵ All of this is classic targeted therapy: find a protein the tumor depends on and shut it down.

The Immune Side of the Story

Here is where the neat classification breaks down. Trastuzumab is an IgG1 antibody, and IgG1 antibodies come equipped with an Fc region, the tail end of the antibody that immune cells recognize. When trastuzumab binds HER2 on a cancer cell, that Fc tail sticks out like a flag, and natural killer cells, macrophages, and other immune effectors grab onto it through their Fc-gamma receptors. This triggers a process called antibody-dependent cellular cytotoxicity, or ADCC, in which natural killer cells release toxic granules that kill the tagged cancer cell.⁶

Research has teased apart which immune cells do what. Natural killer cells are the main drivers of ADCC, directly destroying the antibody-coated tumor cell. Monocytes and macrophages, by contrast, contribute primarily through antibody-dependent cellular phagocytosis, physically engulfing and digesting the cancer cell rather than poisoning it from the outside.⁷ Both of these killing routes are immune-mediated in every meaningful sense: the drug paints the target, and the patient’s own immune system does the destroying.

Beyond these innate immune mechanisms, trastuzumab can also kick-start an adaptive immune response. When macrophages engulf a cancer cell coated with trastuzumab, they chew it up and present fragments of HER2 on their surface to T cells, priming the immune system to recognize HER2-positive cells even without the antibody present. Researchers describe this as a “vaccine-like effect” that activates both innate and adaptive immunity.⁵ That is not something you typically associate with the phrase “targeted therapy.”

Why Your Genetics Affect How Well Trastuzumab Works

If the immune-mediated killing were a minor side effect of trastuzumab, you would expect genetic variation in the immune system to have little impact on how well the drug performs. The opposite is true. The Fc-gamma receptors on immune cells come in slightly different versions depending on the patient’s genetics, and those variants bind the Fc tail of trastuzumab with differing strengths. A large analysis of the NSABP B-31 adjuvant trial found a dose-response relationship: patients who carried the high-affinity version of the FCGR3A receptor on both chromosomes saw the greatest benefit from trastuzumab, patients with one high-affinity and one low-affinity copy got intermediate benefit, and patients homozygous for the low-affinity version benefited the least.⁸

Similar patterns show up with FCGR2A, another Fc-gamma receptor gene. In smaller studies, patients carrying the high-affinity variant of FCGR2A had significantly better pathological response rates and longer progression-free survival on trastuzumab.⁹ These findings are a strong argument that ADCC is not just a laboratory curiosity: it meaningfully contributes to whether trastuzumab controls cancer in real patients. If the drug worked purely by blocking HER2 signaling, the genetics of your immune receptors should not matter.

Another clue comes from tumor-infiltrating lymphocytes, the immune cells already present inside the tumor before treatment starts. A meta-analysis found that patients with higher levels of these immune cells at baseline had significantly better response rates and longer survival when treated with trastuzumab-containing regimens.¹⁰ A tumor that already has an active immune presence seems better primed to take advantage of trastuzumab’s immune-recruiting abilities.

Complement Activation Adds a Third Immune Layer

ADCC and phagocytosis are not the only immune pathways trastuzumab engages. When trastuzumab is combined with pertuzumab, another anti-HER2 antibody that binds a different spot on the receptor, the pair can activate the classical complement pathway. Complement is a cascade of blood proteins that, once triggered, can punch holes directly in the cancer cell’s membrane and also coat the cell in molecules that make phagocytosis more efficient. Research in HER2-positive tumor models found that the combination of trastuzumab and pertuzumab produced both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis, with significantly more tumor-cell engulfment by macrophages than either antibody alone.¹¹ This is yet another mechanism that sits squarely in the immunotherapy column.

How It Got Labeled “Targeted Therapy” in the First Place

Trastuzumab entered clinical use in 1998, when the FDA approved it as the first targeted therapy for HER2-positive metastatic breast cancer.¹² The word “targeted” was revolutionary at the time. Until that point, cancer treatment largely meant chemotherapy and radiation, both of which attack dividing cells indiscriminately. The idea of a drug that homed in on one specific protein was a conceptual breakthrough, and trastuzumab became its poster child. The 2019 Lasker Clinical Research Award recognized its developers for inventing the “first monoclonal antibody that blocks a cancer-causing protein.”¹³

The framing made sense given what was known in the late 1990s. ADCC was recognized but not well characterized for trastuzumab at the time. The clinical narrative centered on shutting down a growth signal. As the immune mechanisms were uncovered in the 2000s and 2010s, the label had already calcified. Expert consensus documents from oncology societies still call trastuzumab a “major breakthrough in targeted therapy.”¹⁴ The classification is not wrong, it is just incomplete.

Pairing Trastuzumab with Checkpoint Inhibitors

If trastuzumab already engages the immune system, it stands to reason that combining it with drugs that further unleash the immune response could amplify its effect. That logic has led to clinical trials pairing trastuzumab with immune checkpoint inhibitors like pembrolizumab. In at least some cases where neither drug worked well on its own, the combination produced clinically meaningful responses, suggesting the two mechanisms can be synergistic.¹⁵ Pembrolizumab works by removing a brake that tumors use to suppress T cells. Trastuzumab, through its vaccine-like priming of anti-HER2 T cells, may give those newly unbridled T cells a specific target. The two drugs complement each other precisely because trastuzumab is doing immunotherapy-like work underneath its targeted therapy label.

Antibody-Drug Conjugates Build on Both Mechanisms

Trastuzumab deruxtecan, often called T-DXd, is a next-generation drug that takes the trastuzumab antibody and attaches a potent chemotherapy payload to it. The antibody portion still binds HER2 and still activates Fc-receptor-mediated killing. But now it also delivers a cell-killing chemical directly into the tumor cell and, through a “bystander effect,” into neighboring cancer cells that may express little or no HER2.¹⁶ The payload is released by enzymes found in the tumor environment, and studies have confirmed that the drug-antibody conjugate still activates Fc-gamma receptors and promotes phagocytosis by macrophages at levels comparable to naked trastuzumab.¹⁷

T-DXd blurs the classification lines even further: it is simultaneously a targeted therapy (it homes in on HER2), an immunotherapy (it activates ADCC and phagocytosis), and a chemotherapy delivery vehicle (it releases a topoisomerase inhibitor). Trying to pick a single category for this drug is an exercise in futility. Yet the classification matters for regulatory pathways, reimbursement, and how clinical trials are designed, so oncologists and regulators continue to negotiate the boundaries.

When the Targeted Mechanism Fails

Resistance to trastuzumab develops through multiple overlapping routes, including changes to the HER2 receptor itself, activation of alternative growth pathways, tumor heterogeneity where only some cancer cells overexpress HER2, and immune evasion.¹⁸ One well-studied resistance mechanism involves mutations in a gene called PIK3CA, which encodes part of the signaling pathway downstream of HER2. When this pathway is mutated to be permanently active, blocking HER2 at the surface no longer shuts off the growth signal. Research has shown that trastuzumab normally disrupts the complex formed by HER2, its partner receptor, and the signaling enzyme, but if that enzyme is mutated, the complex’s disruption does not stop the downstream signal.³

This is where the dual identity becomes practically important. A patient whose tumor has a PIK3CA mutation may get limited benefit from trastuzumab’s signal-blocking mechanism but could still benefit from its immune-mediated killing. Conversely, a patient with a weak innate immune response, perhaps due to low-affinity Fc-gamma receptor variants or an immunosuppressive tumor environment, might rely more heavily on the direct signaling blockade. Understanding which mechanism is carrying the therapeutic weight for a given patient could inform which combination strategies to pursue.

Cardiotoxicity Reveals How the Targeted Mechanism Reaches Beyond the Tumor

One of trastuzumab’s most significant side effects is cardiac dysfunction, and the mechanism behind it reinforces the targeted-therapy classification in an unwelcome way. HER2 is not only found on breast cancer cells; adult heart muscle cells also express it, though at much lower levels. In the heart, HER2 pairs with a related receptor called ErbB4 and responds to a growth factor called neuregulin to maintain the health and survival of cardiac muscle cells. Trastuzumab’s cardiotoxicity appears to stem from blocking this survival signaling in the heart, essentially the same targeted mechanism that makes it effective against cancer, applied to the wrong tissue.¹⁹

The resulting cardiac effects, typically a decline in heart pumping function, are generally reversible once trastuzumab is stopped, unlike the cumulative and often irreversible damage caused by certain chemotherapy drugs. Still, the risk is real enough that patients receiving trastuzumab undergo regular heart function monitoring. The cardiotoxicity primarily arises from ErbB2 signaling blockade compromising the heart muscle’s repair mechanisms.²⁰ Research into engineered antibodies that can block HER2 on cancer cells without interfering with the HER2/ErbB4 survival pathway in cardiac cells is ongoing and could eventually decouple the anticancer effect from the cardiac side effect.

How to Think About the Classification

The honest answer is that the either-or framing of immunotherapy versus targeted therapy was always too simple for monoclonal antibodies. Small-molecule drugs that block HER2 signaling without an antibody backbone, like lapatinib, are purely targeted therapies: they inhibit the protein’s kinase activity and do nothing to recruit immune cells. Checkpoint inhibitors like pembrolizumab are purely immunotherapies: they release brakes on the immune system without targeting a tumor-specific protein. Trastuzumab sits between these poles. Its antibody structure guarantees immune engagement, and its HER2 specificity guarantees targeted signaling disruption. Asking which category it belongs to is like asking whether a spork is a spoon or a fork.

In practice, most oncology textbooks and treatment guidelines file trastuzumab under “targeted therapy” because that was its original conceptual framework and because HER2 testing, the targeted selection of patients whose tumors express the target, is what determines who gets the drug. But immunology-focused researchers increasingly emphasize the immune mechanisms, and combination trials with checkpoint inhibitors treat trastuzumab’s immune activity as a feature to build on rather than an afterthought. If you encounter trastuzumab described as targeted therapy in one source and immunotherapy in another, neither is wrong. They are each describing a real and clinically relevant part of how the drug works.

Macrophages as Underappreciated Effectors

Much of the early immunology research on trastuzumab focused on natural killer cells and ADCC, partly because that mechanism was easier to study in the lab. But macrophage-mediated phagocytosis is getting more attention. Studies have demonstrated that macrophages can engulf and kill cancer cells coated with trastuzumab through direct physical phagocytosis, and this killing pathway may be especially important in solid tumors where natural killer cells have difficulty penetrating.²¹ Tumors are often heavily infiltrated by macrophages, and while those macrophages are frequently co-opted by the tumor into a pro-growth, immunosuppressive state, trastuzumab can redirect them toward cancer-cell destruction. The interplay between trastuzumab and the tumor’s macrophage population is an active area of research that could yield new strategies for boosting the drug’s immune effects without increasing its cardiac risks.