CD24 emerges as the next macrophage checkpoint

Immuno-oncology has been transformed by checkpoint inhibitors that release the brakes on T cells. Yet for many cancers, especially those lacking T-cell infiltration, these therapies deliver limited benefit.

In the search for greater success, attention is increasingly shifting to another arm of the immune system: macrophages.

Pheast Therapeutics is among the companies pursuing this approach. Under the medical leadership of Dr Raphaël Rousseau, Chief Medical Officer, the company is advancing PHST001, an anti-CD24 antibody designed to restore macrophage activity against tumours. The first patient was dosed in a phase I study earlier this year, marking Pheast’s transition into clinical-stage development.

“I joined Pheast as Chief Medical Officer because of its bold focus on macrophage biology and I’m leading clinical development of PHST001, our anti-CD24 macrophage checkpoint inhibitor. In April, we dosed our first patient in a Phase I trial, marking Pheast’s transition to a clinical-stage company.”

Beyond CD47

The concept of macrophage checkpoint inhibition is not new. CD47, another ‘don’t eat me’ signal, prevents macrophages from recognising and engulfing tumour cells and was the first checkpoint of this type to gain serious clinical attention.

CD24 offers a very different profile. It is highly expressed – and in some cancers its encoding gene is amplified – while being absent from red blood cells and platelets. That distinction creates the potential for a better safety margin.

However, CD47 blockade has been constrained by safety issues. The widespread presence of CD47 on red blood cells and platelets leads to dose-limiting effects such as anaemia and thrombocytopenia, which in turn restrict the therapeutic window.

CD24 has a different profile. Rousseau explains: “CD24 offers a very different profile. It is highly expressed – and in some cancers its encoding gene is amplified – while being absent from red blood cells and platelets. That distinction creates the potential for a better safety margin.”

Cancer types in which CD24 is overexpressed are ovarian and endometrial cancers, cholangiocarcinoma and others, with the gene amplified in some cases, making it an attractive target for precision development.

Engineering PHST001

Despite its promise, CD24 presents technical hurdles. The protein is heavily glycosylated, meaning it carries complex sugar chains on its surface. This structural variability creates heterogeneity that can hinder antibody design. PHST001 was engineered specifically to address this challenge.

Another challenge with CD24 is that it is heavily glycosylated, which can complicate antibody targeting.

“Another challenge with CD24 is that it is heavily glycosylated, which can complicate antibody targeting,” Rousseau says. “PHST001 was engineered specifically to bind across the full spectrum of CD24 glycoforms, ensuring consistent blockade of the CD24/Siglec-10 interaction. Importantly, it uses an IgG4 backbone to gently engage macrophages without over-activating the immune system, which may help avoid cytokine release and other safety liabilities.”

These engineering choices reflect lessons learnt from earlier immunotherapies: efficacy must be balanced against safety, particularly when modulating innate immune cells that can drive strong inflammatory responses.

Expanding immuno-oncology beyond T-cell targets

The arrival of T-cell checkpoint inhibitors revolutionised cancer treatment but also highlighted their limitations. Patients whose tumours are ‘cold’ – lacking infiltrating T cells – often derive little benefit. Macrophage checkpoint inhibition offers an orthogonal approach.

“For the last decade, immuno-oncology has been dominated by therapies that unleash T cells,” Rousseau says. “Those treatments can be transformative, but they are not effective in every tumour type, especially in cancers that lack T-cell infiltration or strong antigen presentation. Macrophages are different: they are abundant in virtually all tumours and are naturally equipped to engulf and destroy cancer cells.”

For the last decade, immuno-oncology has been dominated by therapies that unleash T cells.

By releasing inhibitory signals such as CD24, macrophages can be reprogrammed into active effectors. Importantly, this not only results in direct tumour killing but macrophage reactivation can also remodel the tumour microenvironment, enabling T-cell infiltration and amplifying broader immune responses.

“By blocking suppressive signals like CD24, we can flip macrophages from being tumour-supportive to tumour-killing. That doesn’t just shrink tumours directly, it can also remodel the microenvironment, allowing other immune cells to enter,” he adds. “In this way, macrophage checkpoint inhibitors may complement T-cell–focused therapies while also extending immunotherapy to cancers that have historically resisted them.”

From preclinical data to patients

Preclinical studies of PHST001 have demonstrated consistent macrophage reactivation across tumour types. The antibody promoted phagocytosis, triggered durable tumour clearance and, in some models, converted immune-excluded tumours into inflamed ones.

Across multiple tumour types, PHST001 restored macrophage function and triggered durable tumour clearance. In some models, we saw ‘cold’ tumours convert into ‘hot’ tumours once CD24 was blocked.

“The consistency of the preclinical data is what excites me most,” Rousseau says. “Across multiple tumour types, PHST001 restored macrophage function and triggered durable tumour clearance. In some models, we saw ‘cold’ tumours convert into ‘hot’ tumours once CD24 was blocked.”

The ongoing phase I study is dose-escalating in patients with advanced solid tumours. The immediate goal is to establish safety and determine an optimal dose. Expansion cohorts will then focus on tumour types where CD24 is particularly relevant, such as ovarian and triple-negative breast cancer.

“The immediate priority is to establish safety and the optimal dose,” Rousseau explains. “From there, we will begin to explore biological signals of activity – whether we see evidence of macrophage activation or changes in the tumour microenvironment – and then move into expansion cohorts focused on cancers such as ovarian and triple-negative breast cancer where CD24 biology is strongest.”

Strategic lessons

Rousseau has helped to develop a range of modalities, from antibodies and small molecules to engineered T cells and vaccines. He identifies two critical lessons that are guiding the development of PHST001.

First is the importance of precision. “We have learned from past programmes that choosing the right target, designing the right molecule and selecting the right patients are critical,” he says. “With PHST001, we engineered an antibody that works across CD24’s complex glycoforms and designed it with an IgG4 backbone for safety. We’re also embedding biomarker work into our trials from day one to understand, among other things, how CD24 expression relates to clinical response.”

Second is the need for combinations. Just as T-cell checkpoint inhibitors achieved their greatest success in combination with chemotherapy or targeted agents, macrophage checkpoint inhibitors are likely to show their strongest effect when paired with therapies that create pro-phagocytic ‘eat me’ signals.

“Combinations will be essential,” Rousseau says. “Just as checkpoint inhibitors achieved their greatest impact when layered onto chemotherapy or targeted therapies, we expect macrophage checkpoint inhibitors to show the most benefit alongside treatments that create ‘eat me’ signals, such as chemotherapy, radiation, or even other immunotherapies. We are building that thinking into our clinical programme from the outset and combinations will be tested during the Phase I cohort expansions.”

Proof-of-concept for PHST001

In the near-term, Pheast aims to deliver clinical proof-of-concept for PHST001 in cancers where CD24 is amplified and patients urgently need alternatives. At the same time, the company is advancing a discovery pipeline of macrophage-directed therapies, supported by proprietary functional screens that reveal new immune regulators. This work includes programmes in antibody–drug conjugates as well as novel checkpoint targets.

Our vision is to establish macrophage checkpoint blockade as a validated pillar of immuno-oncology.

“Our vision is to establish macrophage checkpoint blockade as a validated pillar of immuno-oncology,” Rousseau says. “In the near term, that means generating clinical proof-of-concept with PHST001 in cancers like ovarian cancer, endometrial cancer and cholangiocarcinoma, where CD24 is overexpressed and its gene is often amplified and patients urgently need new options. We will also be exploring rational combinations with chemotherapy, ADCs and other immune modulators.”

Looking further ahead, he believes macrophage checkpoint inhibitors will become as fundamental as T-cell checkpoint inhibitors. “In five years, I believe macrophage checkpoint inhibitors will be recognised alongside T-cell-directed immunotherapies as the next fundamental approach to treating cancer,” he concludes.