Conventional immune checkpoint inhibitors, such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, can reinvigorate T cells but typically benefit less than 30% of patients. Dual checkpoint blockade improves efficacy yet often triggers severe immune-related adverse events due to systemic T cell activation. Meanwhile, small-molecule immunomodulators like Toll-like receptor (TLR) agonists suffer from rapid clearance and dose-limiting inflammation. Tumor accumulation remains suboptimal, and therapeutic windows are narrow. Based on these challenges, there is an urgent need for deeper research into delivery platforms that can spatiotemporally control immune activation, enhance tumor targeting, and improve both safety and efficacy in cancer immunotherapy.
A new article led by researchers at the Chinese Academy of Sciences and collaborating institutions has been published (DOI: 10.20892/j.issn.2095-3941.2025.0512)in Cancer Biology & Medicine. The work systematically examines polymer-based antibody conjugation technologies, including covalent methods such as carbodiimide chemistry and click chemistry, as well as non-covalent Fc-binding peptide strategies. This editorial covers bispecific antibodies, trispecific antibodies, and antibody–drug conjugates with ultrahigh drug-to-antibody ratios. It highlights how these platforms can improve therapeutic outcomes by enhancing multivalent binding, simplifying assembly, and enabling tumor-specific immune activation.
It also highlights several polymer-enabled advances with concrete data. One polymer-assembled PD1/PDL1 bispecific antibody achieved 90.1% tumor suppression in mouse models while causing less weight loss than free antibodies. A switchable immunomodulator (Sw-IM) uses pH-responsive linkers that remain inactive in circulation but release immune activation only inside the tumor microenvironment, dramatically reducing liver and spleen toxicity. For T cell engagement, a trispecific construct (PDL1/CD3ε/4-1BB) carrying about 11 antibodies per scaffold raised tumor killing from 45% to 80% by stabilizing immune synapses. In the cytotoxic antibody–drug conjugate (ADC) space, a polyglutamic acid-modified anti-PD-L1 conjugate reached a drug-to-antibody ratio of 72—far above the typical limit of 10—which triggers robust immunogenic cell death and damage-associated molecular pattern release. Another CD73-targeting ADC reprogrammed the immunosuppressive adenosine pathway and turned “cold” tumors into “hot” ones, boosting anti-PD-1 efficacy from 21% to 92% tumor suppression. The paper also compares four conjugation chemistries: EDC/NHS amide coupling, maleic anhydride-amine ring-opening amidation, click chemistry (including thiol-maleimide and SPAAC), and Fc-binding peptide-mediated assembly, each with distinct advantages and limitations for clinical translation.
The authors said that polymer platforms give them a completely new way to design cancer immunotherapies. They explained that instead of being limited to one or two targets, they can now assemble multispecific antibodies with precise ratios and add immune stimulators or cytotoxic drugs to the same construct. They added that this flexibility allows them to keep the immune attack focused on the tumor while sparing healthy tissues. They emphasized that this is a major step toward making immunotherapy both more powerful and more tolerable for patients, especially for those who do not respond to current treatments.
These polymer-based tools can be tailored for different cancer types and combined with existing therapies. For solid tumors, ultrahigh drug-loading ADCs may overcome poor accumulation and insufficient immunogenic cell death induction. For hematologic malignancies, lower-toxicity payloads can achieve complete tumor eradication with better patient tolerance. The platforms also support modular assembly of next-generation bispecifics and trispecifics, simplifying manufacturing. As polymer engineering matures, these conjugates could become standard components of combination regimens, working alongside checkpoint inhibitors, cancer vaccines, or cytokines to reshape the tumor microenvironment and drive durable responses. However, the authors note that clinical translation will require better control over polymer dispersity, standardized manufacturing, and careful safety optimization.
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References
DOI
10.20892/j.issn.2095-3941.2025.0512
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0512
Funding information
This study was financially supported by the Ministry of Science and Technology of China (Grant No. 2022YFE0110200), the National Natural Science Foundation of China (Grant Nos. 52573183, 52273157, 52073279, and 52025035), Jilin province (Grant No. 20240305041YY), as well as the Youth Innovation Promotion Association of Chinese Academy of Sciences (Grant No. 2022224).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).