Immunotherapy in Breast Cancer

Unmasking the Camouflage Effect: Mechanisms, Biomarkers, Clinical Evidence and Prognosis

1. Introduction

For decades, breast cancer was regarded as an immunologically “cold” malignancy, one in which the immune system played little part and in which therapy relied on surgery, radiotherapy, cytotoxic chemotherapy, endocrine therapy and HER2-directed agents. That view has changed substantially. Immune checkpoint inhibitors (ICIs), antibodies that block the inhibitory PD-1/PD-L1 axis, are now part of standard care for selected patients with triple-negative breast cancer (TNBC), and they are under active investigation in estrogen receptor-positive (ER+) disease [6,25].

The infographic that frames this essay summarises the concept in a striking metaphor. A tumour cell wears a “camouflage” of PD-L1 protein, which blinds the T-cell that would otherwise destroy it; immunotherapy removes the mask, releasing the “brakes” on the immune system so that T-cells can recognise and kill cancer. The metaphor is a useful teaching device, and this essay uses it as a starting point: it explains the underlying biology, examines the biomarkers that predict benefit, and then develops the clinical insights that the infographic touches on only briefly, namely neoadjuvant and metastatic use, pathologic complete response, survival, toxicity and the open questions that remain.

2. The Camouflage Effect: How Breast Cancer Evades the Immune System

Evasion of immune destruction is recognised as a hallmark of cancer [1]. Tumours accumulate genetic alterations that generate neoantigens, which in principle allow cytotoxic T-cells to identify them as foreign. Over time, however, cancers that survive are those that learn to escape. Several mechanisms contribute, including loss of antigen presentation, recruitment of regulatory T-cells and myeloid-derived suppressor cells, secretion of immunosuppressive cytokines, and, most relevant here, exploitation of inhibitory checkpoint pathways [2,3].

The best-characterised of these pathways involves programmed cell death protein 1 (PD-1), a receptor expressed on activated T-cells, and its ligand PD-L1, which may be expressed on tumour cells and on infiltrating immune cells such as macrophages. When PD-L1 binds PD-1, it transmits an inhibitory signal that dampens T-cell proliferation, cytokine release and cytotoxic activity. In the language of the infographic, the T-cell is “blindfolded”: it is physically present in the tumour but functionally disarmed. The term “camouflage” is a simplification, since the tumour is not strictly invisible to the T-cell; rather, the T-cell is switched off. This distinction matters clinically because it explains why a tumour must already contain T-cells, and ideally pre-existing immune activity, for checkpoint blockade to work.

Breast cancer is immunologically heterogeneous. TNBC and HER2-positive tumours generally carry more tumour-infiltrating lymphocytes (TILs) than luminal tumours, and higher TIL levels are associated with better prognosis and higher response to neoadjuvant chemotherapy in these subtypes [4,5]. This inherent immunogenicity is the principal biological reason why TNBC became the first breast cancer subtype in which immunotherapy succeeded.

3. Mode of Action of Immune Checkpoint Inhibitors

Checkpoint inhibitors are monoclonal antibodies that bind either PD-1 on the T-cell (pembrolizumab, nivolumab) or PD-L1 on the tumour and immune cells (atezolizumab, durvalumab). Both strategies prevent the PD-1/PD-L1 interaction. The inhibitory signal is lifted, and previously exhausted T-cells can regain their capacity to proliferate, secrete interferon-gamma and release cytotoxic granules against tumour cells [3]. The infographic correctly depicts this as the release of the “brakes”; the antibodies do not attack the cancer directly, and their effect depends on an immune response that already exists or can be generated.

Combining ICIs with chemotherapy has a sound rationale. Cytotoxic drugs, particularly anthracyclines, taxanes and platinum agents, can induce immunogenic cell death, release tumour antigens and transiently reduce suppressive cell populations, thereby priming the tumour microenvironment for checkpoint blockade [6]. This is why, in breast cancer, ICIs have been successful almost exclusively in combination with chemotherapy and not as single agents.

4. Biomarkers: Predicting Who Benefits

4.1 PD-L1 expression

PD-L1 is the biomarker highlighted in the infographic, and its role is real but context-dependent. In metastatic TNBC, benefit is concentrated in PD-L1-positive disease. In KEYNOTE-355, pembrolizumab with chemotherapy improved overall survival only in patients with a combined positive score (CPS) of 10 or more, and not in the CPS ≥1 or intention-to-treat populations [17,18]. In IMpassion130, the benefit of atezolizumab was likewise confined to patients with PD-L1 expression on tumour-infiltrating immune cells [14]. By contrast, in early TNBC, KEYNOTE-522 showed benefit irrespective of PD-L1 status, so PD-L1 testing is not used to select patients for the neoadjuvant regimen [7]. The practical lesson is that PD-L1 is a selection tool in the advanced setting but not in the curative setting. Assay, scoring system (CPS versus immune-cell score) and sampling site also differ between trials and are not interchangeable, which complicates testing in routine practice.

4.2 Triple-negative subtype

TNBC, defined by the absence of ER, progesterone receptor and HER2, is the subtype in which immunotherapy has the clearest and most durable benefit, as the infographic states. TNBC is more proliferative, more genomically unstable and more heavily infiltrated by lymphocytes than other subtypes, and until recently had few targeted options, so the arrival of ICIs addressed a major unmet need.

4.3 Tumour mutational burden and TILs

Tumours with a high tumour mutational burden (TMB) generate more neoantigens and are therefore more visible to T-cells. Breast cancer has a relatively low TMB overall, and only a small minority of cases reach the high-TMB threshold [21]. Nevertheless, pembrolizumab has a tissue-agnostic indication for TMB-high solid tumours, and breast cancers that qualify may respond [22]. TILs are an additional, inexpensive and biologically intuitive marker; a high stromal TIL count predicts response to neoadjuvant chemotherapy and better prognosis in TNBC and HER2-positive disease [4,5]. However, neither TMB nor TILs has been validated as a stand-alone predictive test for ICI selection in routine breast cancer practice, and PD-L1 remains the only biomarker used for treatment decisions, and only in the metastatic setting.

5. Clinical Evidence

The following table summarises the pivotal trials discussed in this section.

Trial	Setting	Regimen	Principal finding
KEYNOTE-522	Early TNBC (stage II–III), neoadjuvant then adjuvant	Pembrolizumab + carboplatin/paclitaxel, then AC/EC; adjuvant pembrolizumab	pCR 64.8% vs 51.2%; EFS HR 0.63; 5-year OS 86.6% vs 81.7%
IMpassion031	Early TNBC, neoadjuvant	Atezolizumab + nab-paclitaxel, then AC	pCR 58% vs 41%
GeparNuevo	Early TNBC, neoadjuvant	Durvalumab + nab-paclitaxel, then EC	pCR 53.4% vs 44.2% (not statistically significant)
NeoTRIP	Early TNBC, neoadjuvant	Atezolizumab + carboplatin/nab-paclitaxel	No pCR improvement
IMpassion030	Early TNBC, adjuvant after upfront surgery	Atezolizumab + adjuvant chemotherapy	No benefit; iDFS HR 1.11
IMpassion130	Metastatic TNBC, first line	Atezolizumab + nab-paclitaxel	PD-L1-positive: PFS 7.5 vs 5.0 months; OS 25.0 vs 18.0 months (hierarchically untested)
IMpassion131	Metastatic TNBC, first line	Atezolizumab + paclitaxel	No PFS benefit
KEYNOTE-355	Metastatic TNBC, first line	Pembrolizumab + chemotherapy	CPS ≥10: OS 23.0 vs 16.1 months (HR 0.73)
KEYNOTE-756	High-risk ER+/HER2− early breast cancer	Pembrolizumab + chemotherapy, then pembrolizumab + endocrine therapy	pCR 24.3% vs 15.6%; EFS pending
CheckMate 7FL	High-risk ER+/HER2− early breast cancer	Nivolumab + chemotherapy, then nivolumab + endocrine therapy	pCR increase of about 10.5 points over placebo (13.8%); EFS pending

AC, doxorubicin–cyclophosphamide; EC, epirubicin–cyclophosphamide; pCR, pathologic complete response; EFS, event-free survival; iDFS, invasive disease-free survival; OS, overall survival; PFS, progression-free survival; CPS, combined positive score.

5.1 Neoadjuvant therapy in early TNBC

The landmark trial is KEYNOTE-522, a randomised, double-blind phase 3 study of 1,174 patients with previously untreated stage II or III TNBC. Patients received carboplatin and paclitaxel followed by doxorubicin (or epirubicin) and cyclophosphamide, with pembrolizumab or placebo, and then continued pembrolizumab or placebo after surgery for up to nine cycles. The addition of pembrolizumab increased the pCR rate from 51.2% to 64.8% [7]. Event-free survival improved significantly, with a hazard ratio for event or death of 0.63 at 36 months of follow-up [8]. In 2024, the final analysis, at a median follow-up of 75.1 months, showed an estimated 60-month overall survival of 86.6% with pembrolizumab versus 81.7% with placebo (P = 0.002) [9]. This was the first demonstration that an immunotherapy-based regimen improves overall survival in early TNBC, and it led to regulatory approval of the regimen in the United States and in many other countries.

Other neoadjuvant trials have produced more mixed results. IMpassion031 showed a significant improvement in pCR with atezolizumab plus nab-paclitaxel followed by anthracycline-based chemotherapy (58% versus 41%) [10]. GeparNuevo, which added durvalumab, reported a numerical but statistically non-significant increase in pCR [11], and NeoTRIP, which paired atezolizumab with carboplatin and nab-paclitaxel without an anthracycline, found no pCR benefit [12]. Differences in drug, backbone chemotherapy, sample size and trial design make direct comparison difficult, and KEYNOTE-522 remains the regimen supported by the strongest long-term data.

5.2 The role of adjuvant immunotherapy

A natural question is whether immunotherapy is useful when given only after surgery. The ALEXANDRA/IMpassion030 trial, which randomised 2,199 patients with stage II or III TNBC treated with upfront surgery to adjuvant chemotherapy with or without atezolizumab, found no benefit: the final hazard ratio for invasive disease-free survival was 1.11 (95% CI 0.87–1.42) [13]. This supports giving immunotherapy in the neoadjuvant setting, where the intact tumour and its draining lymph nodes provide a rich antigen source and where treatment response can be assessed. It is also worth noting that KEYNOTE-522 was not designed to separate the contribution of the neoadjuvant and adjuvant phases of therapy, so the optimal duration of treatment remains an open question [9].

5.3 Metastatic TNBC

In the metastatic setting, immunotherapy is used in combination with first-line chemotherapy for PD-L1-positive disease. KEYNOTE-355 showed that pembrolizumab plus chemotherapy prolonged progression-free survival in patients with a CPS ≥10 [17]. The final analysis confirmed an overall survival benefit in this subgroup, with a median of 23.0 versus 16.1 months (hazard ratio 0.73), while the benefit was not significant in the CPS ≥1 or overall populations [18]. IMpassion130 showed improved progression-free survival with atezolizumab and nab-paclitaxel, with a numerically longer overall survival in PD-L1-positive patients that could not be formally tested in the hierarchical design [14,15]. The follow-up IMpassion131 trial, which combined atezolizumab with paclitaxel rather than nab-paclitaxel, did not confirm the benefit [16]. Following these results, the US indication for atezolizumab in TNBC was withdrawn, and pembrolizumab became the principal ICI option for PD-L1-positive metastatic TNBC.

5.4 Beyond triple-negative disease

Because ER-positive disease accounts for the majority of breast cancers, extending ICIs to this group would affect many patients. Two phase 3 trials of high-risk, early-stage ER+/HER2-negative breast cancer have reported on pCR. KEYNOTE-756 found that adding pembrolizumab to neoadjuvant chemotherapy increased the pCR rate from 15.6% to 24.3% [19]; CheckMate 7FL found a comparable absolute increase of about 10 points with nivolumab [20]. In both trials, benefit was greater in PD-L1-positive tumours and in those with low ER expression, a group that behaves biologically like TNBC. Because the event-free survival results that would show a real clinical benefit were still awaited in the sources reviewed, neither regimen should be regarded as standard care for ER+ disease outside clinical trials or specific regulatory approval [19,25]. Data for HER2-positive disease are less mature and no ICI is currently part of standard treatment for this subtype.

6. Clinical Insights and Prognosis

6.1 Pathologic complete response as a prognostic anchor

The infographic notes that immunotherapy “improves pathologic complete response and significantly extends long-term survival”. This statement needs some nuance. pCR, defined as the absence of residual invasive cancer in the breast and axillary nodes after neoadjuvant therapy, is a powerful prognostic marker for the individual patient, particularly in TNBC, where patients who achieve pCR have markedly better outcomes than those with residual disease. At the trial level, however, the relationship between a gain in pCR and a gain in survival is imperfect. The experience of KEYNOTE-522 is reassuring, since an increase in pCR of about 13 percentage points was followed by improvements in event-free and overall survival [7–9]. In contrast, a rise in pCR in the ER+ trials and in GeparNuevo has yet to be translated into proven survival benefit [11,19,20]. Event-free and overall survival data are therefore the definitive measures of success.

6.2 Neoadjuvant versus metastatic use

As the infographic indicates, ICIs are used before surgery to shrink tumours and, in advanced disease, to prolong control. The two settings differ in important ways. In early TNBC the goal is cure, so the benefit-to-risk balance must account for toxicity that may be permanent in patients who would otherwise be cured by standard therapy. In metastatic disease the goal is prolongation of life and disease control, and benefit is limited to the PD-L1-selected population. The neoadjuvant approach also offers a valuable window into biology: response at surgery can guide further therapy, and patients with residual disease remain at higher risk and are a focus of ongoing trials of escalation strategies.

6.3 Immune-related adverse events

Releasing the brakes on the immune system can cause the immune system to attack normal tissue. Immune-related adverse events (irAEs) can affect almost any organ, most often the skin, thyroid, colon, liver and lungs, and rarely the heart, adrenal and pituitary glands, pancreas and nervous system [23]. In KEYNOTE-522, serious treatment-related adverse events occurred in 34.1% of patients receiving pembrolizumab compared with 20.1% receiving placebo, and treatment-related deaths occurred in four versus one patient [9]. Immune-mediated adrenal insufficiency, hypothyroidism and type 1 diabetes can be lifelong even after the immunotherapy is stopped, and this is an important consideration when treating patients with curative intent. For physicians in acute and critical care, the most relevant complications are pneumonitis, myocarditis, severe colitis, hepatitis and adrenal crisis, which may present as unexplained shock, hypoxaemia or arrhythmia in a patient with a recent history of ICI therapy. Early recognition and prompt corticosteroid treatment, with escalation to additional immunosuppression according to guidelines, are central to good outcomes [24].

6.4 Overall prognostic picture

Taken together, the evidence supports three conclusions. First, for patients with stage II–III TNBC, the addition of pembrolizumab to platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab improves pCR, event-free survival and overall survival [7–9]. Second, in PD-L1-positive (CPS ≥10) metastatic TNBC, first-line pembrolizumab with chemotherapy prolongs survival [18]. Third, outside TNBC, immunotherapy remains investigational, with encouraging pCR data that await confirmation by survival endpoints.

7. Challenges and Future Directions

Several challenges lie ahead. The first is patient selection. Not every patient with TNBC benefits, and better predictors than PD-L1 are needed, including multigene immune signatures, TILs, circulating tumour DNA and spatial profiling of the tumour microenvironment. The second is de-escalation and optimisation: it is unclear whether low-risk patients, such as those with small node-negative tumours, can be spared immunotherapy or part of the regimen, and whether patients who achieve pCR need the full adjuvant course [9]. The third is toxicity, particularly permanent endocrinopathies in patients treated with curative intent. The fourth is access and cost. Checkpoint inhibitors are expensive, and PD-L1 testing requires standardised assays and pathology expertise, factors that limit equitable access in many health systems, including resource-constrained ones.

Active areas of research include ICIs combined with antibody–drug conjugates, PARP inhibitors, anti-angiogenic agents and novel checkpoints such as LAG-3, TIGIT and TIM-3; personalised cancer vaccines; and cellular therapies. These strategies aim to convert immunologically “cold” tumours, including ER+ disease, into “hot” tumours that respond to checkpoint blockade.

8. Conclusion

The infographic conveys a simple message: cancer cells use PD-L1 to evade immune attack, and checkpoint inhibitors remove this block so that T-cells can resume their work. This message is biologically sound, if simplified. Clinically, the benefit of immunotherapy in breast cancer is real but selective. It is established in early, high-risk TNBC, where the KEYNOTE-522 regimen improves pCR, event-free survival and overall survival, and in PD-L1-positive metastatic TNBC, where pembrolizumab with chemotherapy prolongs survival. It is not established in the adjuvant-only setting or, as yet, in ER-positive disease. The cost of this benefit is a distinct toxicity profile that can be severe and sometimes permanent, so careful selection, monitoring and multidisciplinary management are essential. The future of the field lies in finding better biomarkers, refining treatment duration, and extending the benefits of immunotherapy beyond the triple-negative subtype, thereby “unleashing the body’s natural defenses” for a broader group of patients.

Note: This essay is an educational summary and not a substitute for current clinical guidelines or product labelling. Trial figures were checked against published abstracts and reports; readers should verify details and the current regulatory status of each regimen against the primary sources before clinical or publication use.

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